Pesticidal compositions and processes related thereto

ABSTRACT

This document discloses molecules having the following formula (“Formula One”): 
     
       
         
         
             
             
         
       
     
     and processes associated therewith.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of, and claims the benefit of, U.S.patent application Ser. No. 13/528,888, filed 21 JUN 2012, which claimspriority from the following U.S. provisional applications: 61/500,685,filed on Jun. 24, 2011; 61/540,056 filed on Sep. 28, 2011; 61/601,077filed on Feb. 21, 2012; and 61/645,267 filed on May 10, 2012; the entirecontents of all of these applications is hereby incorporated byreference into this application.

FIELD OF THE DISCLOSURE

The invention disclosed in this document is related to the field ofprocesses to produce molecules that are useful as pesticides (e.g.,acaricides, insecticides, molluscicides, and nematicides), suchmolecules, and processes of using such molecules to control pests.

BACKGROUND OF THE DISCLOSURE

Pests cause millions of human deaths around the world each year.Furthermore, there are more than ten thousand species of pests thatcause losses in agriculture. The world-wide agricultural losses amountto billions of U.S. dollars each year.

Termites cause damage to all kinds of private and public structures. Theworld-wide termite damage losses amount to billions of U.S. dollars eachyear.

Stored food pests eat and adulterate stored food. The world-wide storedfood losses amount to billions of U.S. dollars each year, but moreimportantly, deprive people of needed food.

There is an acute need for new pesticides. Certain pests are developingresistance to pesticides in current use. Hundreds of pest species areresistant to one or more pesticides. The development of resistance tosome of the older pesticides, such as DDT, the carbamates, and theorganophosphates, is well known. But resistance has even developed tosome of the newer pesticides, for example, imidacloprid.

Therefore, for many reasons, including the above reasons, a need existsfor new pesticides.

DEFINITIONS

The examples given in the definitions are generally non-exhaustive andmust not be construed as limiting the invention disclosed in thisdocument. It is understood that a substituent should comply withchemical bonding rules and steric compatibility constraints in relationto the particular molecule to which it is attached.

“Alkenyl” means an acyclic, unsaturated (at least one carbon-carbondouble bond), branched or unbranched, substituent consisting of carbonand hydrogen, for example, vinyl, allyl, butenyl, pentenyl, and hexenyl.

“Alkenyloxy” means an alkenyl further consisting of a carbon-oxygensingle bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy.

“Alkoxy” means an alkyl further consisting of a carbon-oxygen singlebond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, and tert-butoxy.

“Alkyl” means an acyclic, saturated, branched or unbranched, substituentconsisting of carbon and hydrogen, for example, methyl, ethyl, (C₃)alkylwhich represents n-propyl and isopropyl), (C₄)alkyl which representsn-butyl, sec-butyl, isobutyl, and tert-butyl.

“Alkynyl” means an acyclic, unsaturated (at least one carbon-carbontriple bond), branched or unbranched, substituent consisting of carbonand hydrogen, for example, ethynyl, propargyl, butynyl, and pentynyl.

“Alkynyloxy” means an alkynyl further consisting of a carbon-oxygensingle bond, for example, pentynyloxy, hexynyloxy, heptynyloxy, andoctynyloxy.

“Aryl” means a cyclic, aromatic substituent consisting of hydrogen andcarbon, for example, phenyl, naphthyl, and biphenyl.

“(C_(x)-C_(y))” where the subscripts “x” and “y” are integers such as 1,2, or 3, means the range of carbon atoms for a substituent—for example,(C₁-C₄)alkyl means methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, and tert-butyl, each individually.

“Cycloalkenyl” means a monocyclic or polycyclic, unsaturated (at leastone carbon-carbon double bond) substituent consisting of carbon andhydrogen, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl,norbomenyl, bicyclo[2.2.2]octenyl, tetrahydronaphthyl,hexahydronaphthyl, and octahydronaphthyl.

“Cycloalkenyloxy” means a cycloalkenyl further consisting of acarbon-oxygen single bond, for example, cyclobutenyloxy,cyclopentenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.

“Cycloalkyl” means a monocyclic or polycyclic, saturated substituentconsisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl,cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.

“Cycloalkoxy” means a cycloalkyl further consisting of a carbon-oxygensingle bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,norbornyloxy, and bicyclo[2.2.2]octyloxy.

“Halo” means fluoro, chloro, bromo, and iodo.

“Haloalkoxy” means an alkoxy further consisting of, from one to themaximum possible number of identical or different, halos, for example,fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy, chloromethoxy,trichloromethoxy, 1,1,2,2-tetrafluoroethoxy, and pentafluoroethoxy.

“Haloalkyl” means an alkyl further consisting of, from one to themaximum possible number of, identical or different, halos, for example,fluoromethyl, trifluoromethyl, 2,2-difluoropropyl, chloromethyl,trichloromethyl, and 1,1,2,2-tetrafluoroethyl.

“Heterocyclyl” means a cyclic substituent that may be fully saturated,partially unsaturated, or fully unsaturated, where the cyclic structurecontains at least one carbon and at least one heteroatom, where saidheteroatom is nitrogen, sulfur, or oxygen. In the case of sulfur, thatatom can be in other oxidation states such as a sulfoxide and sulfone.Examples of aromatic heterocyclyls include, but are not limited to,benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl,benzothienyl, benzothiazolyl, cinnolinyl, furanyl, imidazolyl,indazolyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl,triazinyl, and triazolyl. Examples of fully saturated heterocyclylsinclude, but are not limited to, piperazinyl, piperidinyl, morpholinyl,pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl andtetrahydropyranyl. Examples of partially unsaturated heterocyclylsinclude, but are not limited to, 1,2,3,4-tetrahydroquinolinyl,4,5-dihydro-oxazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-isoxazolyl,and 2,3-dihydro-[1,3,4]-oxadiazolyl.

Additional examples include the following

DETAILED DESCRIPTION OF THE DISCLOSURE

This document discloses molecules having the following formula (“FormulaOne”):

wherein:

(a) R1 is selected from

-   -   (1) H, F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, S(C₁-C₈)alkyl,        S(halo(C₁-C₈)alkyl), S(O)(C₁-C₈)alkyl, S(O)(halo(C₁-C₈)alkyl),        S(O)₂(C₁-C₈)alkyl, S(O)₂(halo(C₁-C₈)alkyl), N(R14)(R15),    -   (2) substituted (C₁-C₈)alkyl, wherein said substituted        (C₁-C₈)alkyl has one or more substituents selected from CN and        NO₂,    -   (3) substituted halo(C₁-C₈)alkyl, wherein said substituted        halo(C₁-C₈)alkyl, has one or more substituents selected from CN        and NO₂,    -   (4) substituted (C₁-C₈)alkoxy, wherein said substituted        (C₁-C₈)alkoxy has one or more substituents selected from CN and        NO₂, and    -   (5) substituted halo(C₁-C₈)alkoxy, wherein said substituted        halo(C₁-C₈)alkoxy has one or more substituents selected from CN        and NO₂;

(b) R2 is selected from

-   -   (1) H, F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, S(C₁-C₈)alkyl,        S(halo(C₁-C₈)alkyl), S(O)(C₁-C₈)alkyl, S(O)(halo(C₁-C₈)alkyl),        S(O)₂(C₁-C₈)alkyl, S(O)₂(halo(C₁-C₈)alkyl), N(R14)(R15),    -   (2) substituted (C₁-C₈)alkyl, wherein said substituted        (C₁-C₈)alkyl has one or more substituents selected from CN and        NO₂,    -   (3) substituted halo(C₁-C₈)alkyl, wherein said substituted        halo(C₁-C₈)alkyl, has one or more substituents selected from CN        and NO₂,    -   (4) substituted (C₁-C₈)alkoxy, wherein said substituted        (C₁-C₈)alkoxy has one or more substituents selected from CN and        NO₂, and    -   (5) substituted halo(C₁-C₈)alkoxy, wherein said substituted        halo(C₁-C₈)alkoxy has one or more substituents selected from CN        and NO₂;

(c) R3 is selected from

-   -   (1) H, F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, S(C₁-C₈)alkyl,        S(halo(C₁-C₈)alkyl), S(O)(C₁-C₈)alkyl, S(O)(halo(C₁-C₈)alkyl),        S(O)₂(C₁-C₈)alkyl, S(O)₂(halo(C₁-C₈)alkyl), N(R14)(R15),    -   (2) substituted (C₁-C₈)alkyl, wherein said substituted        (C₁-C₈)alkyl has one or more substituents selected from CN and        NO₂,    -   (3) substituted halo(C₁-C₈)alkyl, wherein said substituted        halo(C₁-C₈)alkyl, has one or more substituents selected from CN        and NO₂,    -   (4) substituted (C₁-C₈)alkoxy, wherein said substituted        (C₁-C₈)alkoxy has one or more substituents selected from CN and        NO₂, and    -   (5) substituted halo(C₁-C₈)alkoxy, wherein said substituted        halo(C₁-C₈)alkoxy has one or more substituents selected from CN        and NO₂;

(d) R4 is selected from

-   -   (1) H, F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, S(C₁-C₈)alkyl,        S(halo(C₁-C₈)alkyl), S(O)(C₁-C₈)alkyl, S(O)(halo(C₁-C₈)alkyl),        S(O)₂(C₁-C₈)alkyl, S(O)₂(halo(C₁-C₈)alkyl), N(R14)(R15),    -   (2) substituted (C₁-C₈)alkyl, wherein said substituted        (C₁-C₈)alkyl has one or more substituents selected from CN and        NO₂,    -   (3) substituted halo(C₁-C₈)alkyl, wherein said substituted        halo(C₁-C₈)alkyl, has one or more substituents selected from CN        and NO₂,    -   (4) substituted (C₁-C₈)alkoxy, wherein said substituted        (C₁-C₈)alkoxy has one or more substituents selected from CN and        NO₂, and    -   (5) substituted halo(C₁-C₈)alkoxy, wherein said substituted        halo(C₁-C₈)alkoxy has one or more substituents selected from CN        and NO₂;

(e) R5 is selected from

-   -   (1) H, F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, S(C₁-C₈)alkyl,        S(halo(C₁-C₈)alkyl), S(O)(C₁-C₈)alkyl, S(O)(halo(C₁-C₈)alkyl),        S(O)₂(C₁-C₈)alkyl, S(O)₂(halo(C₁-C₈)alkyl), N(R14)(R15),    -   (2) substituted (C₁-C₈)alkyl, wherein said substituted        (C₁-C₈)alkyl has one or more substituents selected from CN and        NO₂,    -   (3) substituted halo(C₁-C₈)alkyl, wherein said substituted        halo(C₁-C₈)alkyl, has one or more substituents selected from CN        and NO₂,    -   (4) substituted (C₁-C₈)alkoxy, wherein said substituted        (C₁-C₈)alkoxy has one or more substituents selected from CN and        NO₂, and    -   (5) substituted halo(C₁-C₈)alkoxy, wherein said substituted        halo(C₁-C₈)alkoxy has one or more substituents selected from CN        and NO₂;

(f) R6 is a (C₁-C₈)haloalkyl;

(g) R7 is selected from H, F, Cl, Br, I, OH, (C₁-C₈)alkoxy, andhalo(C₁-C₈)alkoxy;

(h) R8 is selected from H, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, OR14, andN(R14)(R15);

(i) R9 is selected from H, F, Cl, Br, I, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl,(C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, OR14, and N(R14)(R15);

(j) R10 is selected from

-   -   (1) (u), H, F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl,        halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy,        cyclo(C₃-C₆)alkyl, S(C₁-C₈)alkyl, S(halo(C₁-C₈)alkyl),        S(O)(C₁-C₈)alkyl, S(O)(halo(C₁-C₈)alkyl), S(O)₂(C₁-C₈)alkyl,        S(O)₂(halo(C₁-C₈)alkyl), NR14R15, C(═O)H, C(═O)N(R14)(R15),        CN(R14)(R15)(═NOH), (C═O)O(C₁-C₈)alkyl, (C═O)OH, heterocyclyl,        (C₂-C₈)alkenyl, halo(C₂-C₈)alkenyl, (C₂-C₈)alkynyl,    -   (2) substituted (C₁-C₈)alkyl, wherein said substituted        (C₁-C₈)alkyl has one or more substituents selected from OH,        (C₁-C₈)alkoxy, S(C₁-C₈)alkyl, S(O)(C₁-C₈)alkyl,        S(O)₂(C₁-C₈)alkyl, NR14R15, and    -   (3) substituted halo(C₁-C₈)alkyl, wherein said substituted        halo(C₁-C₈)alkyl, has one or more substituents selected from        (C₁-C₈)alkoxy, S(C₁-C₈)alkyl, S(O)(C₁-C₈)alkyl,        S(O)₂(C₁-C₈)alkyl, and N(R14)(R15);

(k) R11 is selected from (u), substituted (C₁-C₈)alkyl, C(═O)OH,C(═O)O(C₁-C₈)alkyl, C(═O)(substituted-(C₁-C₈)alkyl), C(═O)O(substituted(C₁-C₈)alkyl), C(═O)N(R14)(R15), C(═O)heterocyclyl, C(═O)(substitutedheterocyclyl), C(═S)N(R14)(R15), C(═S)heterocyclyl, C(═S)(substitutedheterocyclyl), (C₁-C₈)alkylN(R11a)(C(═X11)R11b), N(11a)(11d),ON(11c)(11d), halo(C₁-C₈)alkyl, (C₁-C₈)alkyl,(C₁-C₈)alkylN(H)(heterocyclyl), (C₁-C₈)alkyl(N(R15))(C═O)O(C₁-C₈)alkyl,(C₁-C₈)alkyl(R14)(R15), N(H)N(H)(heterocyclyl), B(OH)₂,(C₁-C₈)alkylN(R11a)(C(═X11)R14),(C₁-C₈)alkylN(R11a)(C(═X11)N(R14)(R15)),(C₁-C₈)alkylN(R11a)(C(═X11)OR14), substituted or unsubstitutedheterocyclyl, C(═O)N(R14)(N(R16)(R17),C(═O)N(R14)((C₁-C₈)alkylC(═O)N(R14)N(R14)(R15)),C(═O)N(R14)((C₁-C₈)alkylC(═O)N(R14)(R15)),C(═S)N(R14)((C₁-C₈)alkylC(═S)N(R14)(R15)),C(═S)N(R14)((C₁-C₈)alkylC(═O)N(R14)(R15)),C(═O)N(R14)((C₁-C₈)alkylC(═S)N(R14)(R15)),C(═O)N(R14)((C₁-C₈)alkylC(═O)(R15),

-   -   (1) wherein each said substituted (C₁-C₈)alkyl has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, aryl,        substituted aryl, heterocyclyl, substituted heterocyclyl,        wherein each said substituted aryl has one or more substituents        selected from F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl,        halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy,        S(C₁-C₈)alkyl, S(halo(C₁-C₈)alkyl), N((C₁-C₈)alkyl)₂ (wherein        each (C₁-C₈)alkyl is independently selected), and oxo,    -   (2) wherein each said substituted heterocyclyl has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl,        halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy,        S(C₁-C₈)alkyl, S(halo(C₁-C₈)alkyl), N((C₁-C₈)alkyl)₂ (wherein        each (C₁-C₈)alkyl is independently selected), C(═O)(C₁-C₈)alkyl,        C(═O)(C₃-C₆)cycloalkyl, S(═O)₂(C₁-C₈)alkyl, NR14R15, and oxo,    -   (3) wherein R11a is selected from H, (C₁-C₈)alkyl, and        (C₁-C₈)alkyl-heterocyclyl, R14, C(X11)R14, (C₁-C₈)alkylR14    -   (4) wherein R11b is selected from (C₁-C₈)alkyl,        cyclo(C₃-C₆)alkyl, halo(C₁-C₈)alkyl, heterocyclyl,        substituted-heterocyclyl (where said substituents are one or        more of F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, S(C₁-C₈)alkyl,        S(halo(C₁-C₈)alkyl), N((C₁-C₈)alkyl)₂ (wherein each (C₁-C₈)alkyl        is independently selected), and oxo), (C₁-C₈)alkylS(C₁-C₈)alkyl,        (C₁-C₈)alkylS(O)(C₁-C₈)alkyl, (C₁-C₈)alkylS(O)₂(C₁-C₈)alkyl,        N(R11c)(R11d), O(C₁-C₈)alkyl, Oheterocyclyl,        O-substituted-heterocyclyl (where said substituents are one or        more of F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, S(C₁-C₈)alkyl,        S(halo(C₁-C₈)alkyl), N((C₁-C₈)alkyl)₂ (wherein each (C₁-C₈)alkyl        is independently selected), and oxo), C(═O)OR11d,        C(═O)N(R11c)(R11d), C(═O)(R11d)aryl, substituted aryl (where        said substituents are one or more of F, Cl, Br, I, CN, NO₂,        (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy,        halo(C₁-C₈)alkoxy, S(C₁-C₈)alkyl, S(halo(C₁-C₈)alkyl),        N((C₁-C₈)alkyl)₂ (wherein each (C₁-C₈)alkyl is independently        selected),    -   (5) wherein X11 is O or S,    -   (6) wherein R11c is selected from H,    -   (7) wherein R11d is selected from H, (C₁-C₈)alkyl,        (C₁-C₈)alkenyl, halo(C₁-C₈)alkyl, heterocyclyl,        substituted-heterocyclyl (where said substituents are one or        more of F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl,        (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, S(C₁-C₈)alkyl,        S(halo(C₁-C₈)alkyl), N((C₁-C₈)alkyl)₂ (wherein each (C₁-C₈)alkyl        is independently selected), and oxo),        N(H)(C(═O)cyclo(C₃-C₆)alkyl), N(H)(C(═O)halo(C₁-C₈)alkyl),    -   (8) wherein optionally R11c and R11d along with N form a 5, 6,        7, or 8 membered ring that may optionally further contain 1, 2,        or 3, additional heteroatoms selected from O, N, or S, in the        ring;

(l) R12 is selected from (v), H, F, Cl, Br, I, CN, (C₁-C₈)alkyl,halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy, andcyclo(C₃-C₆)alkyl;

(m) R13 is selected from (v), H, F, Cl, Br, I, CN, (C₁-C₈)alkyl,halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy, and halo(C₁-C₈)alkoxy;

(n) each R14 is independently selected from H, (C₁-C₈)alkyl,(C₁-C₈)alkenyl, substituted (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, substitutedhalo(C₁-C₈)alkyl), (C₁-C₈)alkoxy, cyclo(C₃-C₆)alkyl, aryl,substituted-aryl, (C₁-C₈)alkyl-aryl, (C₁-C₈)alkyl-(substituted-aryl),O—(C₁-C₈)alkyl-aryl, O—(C₁-C₈)alkyl-(substituted-aryl), heterocyclyl,substituted-heterocyclyl, (C₁-C₈)alkyl-heterocyclyl,(C₁-C₈)alkyl-(substituted-heterocyclyl), O—(C₁-C₈)alkyl-heterocyclyl,O—(C₁-C₈)alkyl-(substituted-heterocyclyl), N(R16)(R17),(C₁-C₈)alkyl-C(═O)N(R16)(R17), C(═O)(C₁-C₈)alkyl,C(═O)(halo(C₁-C₈)alkyl), C(═O)(C₃-C₆)cycloalkyl,(C₁-C₈)alkyl-C(═O)O(C₁-C₈)alkyl, C(═O)H

-   -   wherein each said substituted (C₁-C₈)alkyl has one or more        substituents selected from CN, and NO₂,    -   wherein each said substituted halo(C₁-C₈)alkyl), has one or more        substituents selected from CN, and NO₂,    -   wherein each said substituted-aryl has one or more substituents        selected from F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl,        halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy,        S(C₁-C₈)alkyl, S(halo(C₁-C₈)alkyl), N((C₁-C₈)alkyl)₂ (wherein        each (C₁-C₈)alkyl is independently selected), and oxo, and    -   wherein each said substituted-heterocyclyl has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl,        halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy,        (C₃-C₆)cycloalkyl S(C₁-C₈)alkyl, S(halo(C₁-C₈)alkyl),        N((C₁-C₈)alkyl)₂ (wherein each (C₁-C₈)alkyl is independently        selected), heterocyclyl, C(═O)(C₁-C₈)alkyl, C(═O)O(C₁-C₈)alkyl,        and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be        further substituted with one or more of F, Cl, Br, I, CN, and        NO₂);

(o) each R15 is independently selected from H, (C₁-C₈)alkyl,(C₁-C₈)alkenyl, substituted (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, substitutedhalo(C₁-C₈)alkyl), (C₁-C₈)alkoxy, cyclo(C₃-C₆)alkyl, aryl,substituted-aryl, (C₁-C₈)alkyl-aryl, (C₁-C₈)alkyl-(substituted-aryl),O—(C₁-C₈)alkyl-aryl, O—(C₁-C₈)alkyl-(substituted-aryl), heterocyclyl,substituted-heterocyclyl, (C₁-C₈)alkyl-heterocyclyl,(C₁-C₈)alkyl-(substituted-heterocyclyl), O—(C₁-C₈)alkyl-heterocyclyl,O—(C₁-C₈)alkyl-(substituted-heterocyclyl), N(R16)(R17),(C₁-C₈)alkyl-C(═O)N(R16)(R17), C(═O)(C₁-C₈)alkyl,C(═O)(halo(C₁-C₈)alkyl), C(═O)(C₃-C₆)cycloalkyl,(C₁-C₈)alkyl-C(═O)O(C₁-C₈)alkyl, C(═O)H

-   -   wherein each said substituted (C₁-C₈)alkyl has one or more        substituents selected from CN, and NO₂,    -   wherein each said substituted halo(C₁-C₈)alkyl), has one or more        substituents selected from CN, and NO₂,    -   wherein each said substituted-aryl has one or more substituents        selected from F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl,        halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy,        S(C₁-C₈)alkyl, S(halo(C₁-C₈)alkyl), N((C₁-C₈)alkyl)₂ (wherein        each (C₁-C₈)alkyl is independently selected), and oxo, and    -   wherein each said substituted-heterocyclyl has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl,        halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy,        (C₃-C₆)cycloalkyl S(C₁-C₈)alkyl, S(halo(C₁-C₈)alkyl),        N((C₁-C₈)alkyl)₂ (wherein each (C₁-C₈)alkyl is independently        selected), heterocyclyl, C(═O)(C₁-C₈)alkyl, C(═O)O(C₁-C₈)alkyl,        and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be        further substituted with one or more of F, Cl, Br, I, CN, and        NO₂);

(p) each R16 is independently selected from H, (C₁-C₈)alkyl,substituted-(C₁-C₈)alkyl, halo(C₁-C₈)alkyl,substituted-halo(C₁-C₈)alkyl, cyclo(C₃-C₆)alkyl, aryl, substituted-aryl,(C₁-C₈)alkyl-aryl, (C₁-C₈)alkyl-(substituted-aryl), O—(C₁-C₈)alkyl-aryl,O—(C₁-C₈)alkyl-(substituted-aryl), heterocyclyl,substituted-heterocyclyl, (C₁-C₈)alkyl-heterocyclyl,(C₁-C₈)alkyl-(substituted-heterocyclyl), O—(C₁-C₈)alkyl-heterocyclyl,O—(C₁-C₈)alkyl-(substituted-heterocyclyl), O—(C₁-C₈)alkyl

-   -   wherein each said substituted (C₁-C₈)alkyl has one or more        substituents selected from CN, and NO₂,    -   wherein each said substituted halo(C₁-C₈)alkyl), has one or more        substituents selected from CN, and NO₂,    -   wherein each said substituted-aryl has one or more substituents        selected from F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl,        halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy,        S(C₁-C₈)alkyl, S(halo(C₁-C₈)alkyl), N((C₁-C₈)alkyl)₂ (wherein        each (C₁-C₈)alkyl is independently selected), and oxo, and    -   wherein each said substituted-heterocyclyl has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl,        halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy,        S(C₁-C₈)alkyl, S(halo(C₁-C₈)alkyl), N((C₁-C₈)alkyl)₂ (wherein        each (C₁-C₈)alkyl is independently selected), and oxo;

(q) each R17 is independently selected from H, (C₁-C₈)alkyl,substituted-(C₁-C₈)alkyl, halo(C₁-C₈)alkyl,substituted-halo(C₁-C₈)alkyl, cyclo(C₃-C₆)alkyl, aryl, substituted-aryl,(C₁-C₈)alkyl-aryl, (C₁-C₈)alkyl-(substituted-aryl), O—(C₁-C₈)alkyl-aryl,O—(C₁-C₈)alkyl-(substituted-aryl), heterocyclyl,substituted-heterocyclyl, (C₁-C₈)alkyl-heterocyclyl,(C₁-C₈)alkyl-(substituted-heterocyclyl), O—(C₁-C₈)alkyl-heterocyclyl,O—(C₁-C₈)alkyl-(substituted-heterocyclyl), O—(C₁-C₈)alkyl

-   -   wherein each said substituted (C₁-C₈)alkyl has one or more        substituents selected from CN, and NO₂,    -   wherein each said substituted halo(C₁-C₈)alkyl), has one or more        substituents selected from CN, and NO₂,    -   wherein each said substituted-aryl has one or more substituents        selected from F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl,        halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy,        S(C₁-C₈)alkyl, S(halo(C₁-C₈)alkyl), N((C₁-C₈)alkyl)₂ (wherein        each (C₁-C₈)alkyl is independently selected), and oxo, and    -   wherein each said substituted-heterocyclyl has one or more        substituents selected from F, Cl, Br, I, CN, NO₂, (C₁-C₈)alkyl,        halo(C₁-C₈)alkyl, (C₁-C₈)alkoxy, halo(C₁-C₈)alkoxy,        S(C₁-C₈)alkyl, S(halo(C₁-C₈)alkyl), N((C₁-C₈)alkyl)₂ (wherein        each (C₁-C₈)alkyl is independently selected), and oxo;

(r) X1 is selected from N and CR12;

(s) X2 is selected from N, CR9, and CR13;

(t) X3 is selected from N and CR9;

(u) R10 and R11 together form a linkage containing 3 to 4 atoms selectedfrom C, N, O, and S, wherein said linkage connects back to the ring toform a 5 to 6 member saturated or unsaturated cyclic ring, wherein saidlinkage has at least one substituent X4 wherein X4 is selected from F,Cl, Br, I, R14, N(R14)(R15), N(R14)(C(═O)R14), N(R14)(C(═S)R14),N(R14)(C(═O)N(R14)(R14)), N(R14)(C(═S)N(R14)(R14)),N(R14)(C(═O)N(R14)((C₁-C₈)alkenyl)),N(R14)(C(═S)N(R14)((C₁-C₈)alkenyl)), oxo, C(═O)(C₁-C₈)alkylN(R14)(R14),(C₁-C₈)alkylC(═O)N(R14)R(15), wherein each R14 is independentlyselected; and

(v) R12 and R13 together form a linkage containing 3 to 4 atoms selectedfrom C, N, O, and S, wherein said linkage connects back to the ring toform a 5 to 6 member saturated or unsaturated cyclic ring, wherein saidlinkage has at least one substituent X4 wherein X4 is selected from R14,N(R14)(R15), N(R14)(C(═O)R14), N(R14)(C(═S)R14),N(R14)(C(═O)N(R14)(R14)), N(R14)(C(═S)N(R14)(R14)),N(R14)(C(═O)N(R14)((C₁-C₈)alkenyl)),N(R14)(C(═S)N(R14)((C₁-C₈)alkenyl)), wherein each R14 is independentlyselected.

In another embodiment of this invention R1 may be selected from anycombination of one or more of the following—H, F, Cl, Br, I, CN, NO₂,methyl, ethyl, (C₃)alkyl, (C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl,(C₈)alkyl, halomethyl, haloethyl, halo(C₃)alkyl, halo(C₄)alkyl,halo(C₅)alkyl, halo(C₆)alkyl, halo(C₇)alkyl, halo(C₈)alkyl, methoxy,ethoxy, (C₃)alkoxy, (C₄)alkoxy, (C₅)alkoxy, (C₆)alkoxy, (C₇)alkoxy,(C₈)alkoxy, halomethoxy, haloethoxy, halo(C₃)alkoxy, halo(C₄)alkoxy,halo(C₅)alkoxy, halo(C₆)alkoxy, halo(C₇)alkoxy, and halo(C₈)alkoxy.

In another embodiment of this invention R2 may be selected from anycombination of one or more of the following—H, F, Cl, Br, I, CN, NO₂,methyl, ethyl, (C₃)alkyl, (C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl,(C₈)alkyl, halomethyl, haloethyl, halo(C₃)alkyl, halo(C₄)alkyl,halo(C₅)alkyl, halo(C₆)alkyl, halo(C₇)alkyl, halo(C₈)alkyl, methoxy,ethoxy, (C₃)alkoxy, (C₄)alkoxy, (C₅)alkoxy, (C₆)alkoxy, (C₇)alkoxy,(C₈)alkoxy, halomethoxy, haloethoxy, halo(C₃)alkoxy, halo(C₄)alkoxy,halo(C₅)alkoxy, halo(C₆)alkoxy, halo(C₇)alkoxy, and halo(C₈)alkoxy.

In another embodiment of this invention R3 may be selected from anycombination of one or more of the following—H, F, Cl, Br, I, CN, NO₂,methyl, ethyl, (C₃)alkyl, (C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl,(C₈)alkyl, halomethyl, haloethyl, halo(C₃)alkyl, halo(C₄)alkyl,halo(C₅)alkyl, halo(C₆)alkyl, halo(C₇)alkyl, halo(C₈)alkyl, methoxy,ethoxy, (C₃)alkoxy, (C₄)alkoxy, (C₅)alkoxy, (C₆)alkoxy, (C₇)alkoxy,(C₈)alkoxy, halomethoxy, haloethoxy, halo(C₃)alkoxy, halo(C₄)alkoxy,halo(C₅)alkoxy, halo(C₆)alkoxy, halo(C₇)alkoxy, and halo(C₈)alkoxy.

In another embodiment of this invention R4 may be selected from anycombination of one or more of the following—H, F, Cl, Br, I, CN, NO₂,methyl, ethyl, (C₃)alkyl, (C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl,(C₈)alkyl, halomethyl, haloethyl, halo(C₃)alkyl, halo(C₄)alkyl,halo(C₅)alkyl, halo(C₆)alkyl, halo(C₇)alkyl, halo(C₈)alkyl, methoxy,ethoxy, (C₃)alkoxy, (C₄)alkoxy, (C₅)alkoxy, (C₆)alkoxy, (C₇)alkoxy,(C₈)alkoxy, halomethoxy, haloethoxy, halo(C₃)alkoxy, halo(C₄)alkoxy,halo(C₅)alkoxy, halo(C₆)alkoxy, halo(C₇)alkoxy, and halo(C₈)alkoxy.

In another embodiment of this invention R5 may be selected from anycombination of one or more of the following—H, F, Cl, Br, I, CN, NO₂,methyl, ethyl, (C₃)alkyl, (C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl,(C₈)alkyl, halomethyl, haloethyl, halo(C₃)alkyl, halo(C₄)alkyl,halo(C₅)alkyl, halo(C₆)alkyl, halo(C₇)alkyl, halo(C₈)alkyl, methoxy,ethoxy, (C₃)alkoxy, (C₄)alkoxy, (C₅)alkoxy, (C₆)alkoxy, (C₇)alkoxy,(C₈)alkoxy, halomethoxy, haloethoxy, halo(C₃)alkoxy, halo(C₄)alkoxy,halo(C₅)alkoxy, halo(C₆)alkoxy, halo(C₇)alkoxy, and halo(C₈)alkoxy.

In another embodiment of this invention R2 and R4 are selected from F,Cl, Br, I, CN, and NO₂ and R1, R3, and R5 are H.

In another embodiment of this invention R2, R3, and R4 are selected fromF, Cl, Br, I, CN, and NO₂ and R1, and R5 are H.

In another embodiment of this invention R2, R3, and R4 are independentlyselected from F and Cl and R1 and R5 are H.

In another embodiment of this invention R1 is selected from Cl and H.

In another embodiment of this invention R2 is selected from CF₃, CH₃,Cl, F, and H.

In another embodiment of this invention R3 is selected from OCH₃, CH₃,F, Cl, or H.

In another embodiment of this invention R4 is selected from CF₃, CH₃,Cl, F, and H.

In another embodiment of this invention R5 is selected from F, Cl, andH.

In another embodiment of this invention R6 may be selected from anycombination of one or more of the following—halomethyl, haloethyl,halo(C₃)alkyl, halo(C₄)alkyl, halo(C₅)alkyl, halo(C₆)alkyl,halo(C₇)alkyl, and halo(C₈)alkyl.

In another embodiment of this invention R6 is trifluoromethyl.

In another embodiment of this invention R7 may be selected from anycombination of one or more of the following—H, F, Cl, Br, and I.

In another embodiment of this invention R7 is selected from H, OCH₃, andOH.

In another embodiment of this invention R8 may be selected from anycombination of one or more of the following—H, methyl, ethyl, (C₃)alkyl,(C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl, (C₈)alkyl, halomethyl,haloethyl, halo(C₃)alkyl, halo(C₄)alkyl, halo(C₅)alkyl, halo(C₆)alkyl,halo(C₇)alkyl, and halo(C₈)alkyl.

In another embodiment of this invention R8 is selected from CH₃ and H.

In another embodiment of this invention R9 may be selected from anycombination of one or more of the following—H, F, Cl, Br, I, methyl,ethyl, (C₃)alkyl, (C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl, (C₈)alkyl,halomethyl, haloethyl, halo(C₃)alkyl, halo(C₄)alkyl, halo(C₅)alkyl,halo(C₆)alkyl, halo(C₇)alkyl, halo(C₈)alkyl, methoxy, ethoxy,(C₃)alkoxy, (C₄)alkoxy, (C₅)alkoxy, (C₆)alkoxy, (C₇)alkoxy, (C₈)alkoxy,halomethoxy, haloethoxy, halo(C₃)alkoxy, halo(C₄)alkoxy, halo(C₅)alkoxy,halo(C₆)alkoxy, halo(C₇)alkoxy, and halo(C₈)alkoxy.

In another embodiment of this invention R10 may be selected from anycombination of one or more of the following—H, F, Cl, Br, I, CN, methyl,ethyl, (C₃)alkyl, (C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl, (C₈)alkyl,halomethyl, haloethyl, halo(C₃)alkyl, halo(C₄)alkyl, halo(C₅)alkyl,halo(C₆)alkyl, halo(C₇)alkyl, halo(C₈)alkyl, methoxy, ethoxy,(C₃)alkoxy, (C₄)alkoxy, (C₅)alkoxy, (C₆)alkoxy, (C₇)alkoxy, (C₈)alkoxy,halomethoxy, haloethoxy, halo(C₃)alkoxy, halo(C₄)alkoxy, halo(C₅)alkoxy,halo(C₆)alkoxy, halo(C₇)alkoxy, halo(C₈)alkoxy, cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

In another embodiment of this invention R10 may be selected from anycombination of one or more of the following—H, Cl, Br, CH₃, and CF₃.

In another embodiment of this invention R10 is selected from Br,C(═NOH)NH₂, C(═O)H, C(═O)NH₂, C(═O)OCH₂CH₃, C(═O)OH, CF₃, CH₂CH₃, CH₂OH,CH3, Cl, CN, F, H, NH₂, NHC(═O)H, NHCH₃, NO₂, OCH₃, OCHF₂, and pyridyl.

In another embodiment of this invention R11 may be selected from anycombination of one or more of thefollowing—C(═O)(substituted-(C₁-C₈)alkyl), C(═O)N(R14)(R15),C(═O)heterocyclyl, and C(═O)(substituted-heterocyclyl).

In another embodiment of this invention R11 is C(═O)morpholinyl.

In another embodiment of this invention R11 may be selected from anycombination of CH₂N(H)C(═O)CH₃, CH₂N(H)C(═O)cyclopropyl,CH₂N(H)C(═O)CH₂CF₃, CH₂N(H)C(═O)CH₂CH₃, CH₂N(H)C(═O)C(CH₃)₃,CH₂N(H)C(═O)(chloropyridyl), CH₂N(H)C(═O)CH₂(chloropyridyl),CH₂N(H)C(═O)CH₂CH₂SCH₃, N(H)C(═O)(pyridyl),CH₂N(CH₂pyridyl)C(═O)cyclopropyl, CH₂N(H)C(═O)N(H)(CH₂CH₃),CH₂N(H)C(═O)morpholinyl, CH₂N(H)C(═O)N(H)(pyridyl), CH₂N(H)C(═O)NH₂,CH₂N(H)C(═O)NH(CH₂CH₃), CH₂N(H)C(═O)NH(CH₂CHCH₂), CH₂N(H)C(═O)OC(CH₃)₃,CH₂N(H)C(═O)O(chlorophenyl), CH₂N(H)C(═O)(C═O)OCH₃,CH₂N(H)C(═O)(C═O)N(H)CH₂CF₃, CH₂N(H)(pyridyl), N(H)N(H)C(═O)cyclopropyl,N(H)N(H)C(═O)CH₂CF₃, ON(H)C(═O)cyclopropyl, and ON(H)C(═O)CH₂CF₃.

In another embodiment of this invention R11 may be selected from anycombination of 1,2,4-triazolyl, 1,2,4-triazolyl-C(═O)cyclopropyl,1,2,4-triazolyl-C(═O)CH₃, 1,2,-methyltriazolyl,1,2,4-triazolyl-N(C(═O)cyclopropyl)₂,1,2,4-triazolylN(H)(C(═O)cyclopropyl), 1,2,4-triazolylNH₂,1,2,4-triazolyl-NO₂, 1,2,4-triazolylS(O)₂CH₃, 1,2,4-triazolylSCH₃,C(═O)(morpholinyl), C(═O)N(CH₃)(CH₃), C(═O)N(H)(CH(CH₃)chloropyridinyl),C(═O)N(H)(CH₂C(═O)N(CH₃)(CH₂CF₃)), C(═O)N(H)(CH₂-benzothiazolyl),C(═O)N(H)(CH₂C(═O)N(H)(CH₂CF₃)), C(═O)N(H)(CH₂C(═O)N(H)(CH₂CH═CH₂)),C(═O)N(H)(CH₂C(═O)N(H)(cyclopropyl)), C(═O)N(H)(CH₂C(═O)N(H)(N(CH₃)₂)),C(═O)N(H)(CH₂C(═O)N(H)(OCH₃)), C(═O)N(H)(CH₂C(═O)N(H)(thietanyl)),C(═O)N(H)(CH₂C(═O)N(H)(thietanyl-dioxide)) C(═O)N(H)(CH₂C(═O)OC(CH₃)₃),C(═O)N(H)(CH₂C(═S)N(H)(CH₂CF₃)), C(═O)N(H)(CH₂CF₃),C(═O)N(H)(CH₂CH₂-chloropyridinyl) C(═O)N(H)(CH₂-furanyl),C(═O)N(H)(CH₂-methylimidazolyl) C(═O)N(H)(CH₂-cyclopropyloxadiazolyl),C(═O)N(H)(CH₂-phenyl), C(═O)N(H)(CH₂-trifluoromethylphenyl),C(═O)N(H)(CH₂-fluorophenyl), C(═O)N(H)(CH₂-pyrazinyl),C(═O)N(H)(CH₂-trifluoromethylpyridinyl), C(═O)N(H)(CH₂-chloropyridinyl),C(═O)N(H)(CH₂-pyridinyl-NO₂), C(═O)N(H)(CH₂-pyridinyl-OCH₃),C(═O)N(H)(CH₂-pyrimidinyl), C(═O)N(H)(CH₂-tetrahydrofuranyl),C(═O)N(H)(CH₂-chlorothiazolyl), C(═O)N(H)(CH₃), C(═O)NH₂,C(═O)N(H)(N(CH₃)(fluorophenyl)), C(═O)N(H)(N(H)(fluorophenyl)),C(═O)N(H)(OCH₂-chloropyridinyl), C(═O)N(H)(piperidinyl),C(═O)N(H)(piperidinylC(═O)CH₂CF₃), C(═O)N(H)(piperidinyl-CH₂CN),C(═O)N(H)(piperidinylC(═O)CH₃), C(═O)N(H)(piperidinylCH₂CH₂OH),C(═O)N(H)(piperidinyl-oxetanyl), C(═O)N(H)(chloropyridinyl),C(═O)N(H)(CH₂-tetrahydropyranyl), C(═O)N(H)(thietanyl),C(═O)N(H)(thietanyl-dioxide), C(═O)N(H)(thietanyl-oxide),C(═O)N(H)(CH₂-pyrazinyl) C(═O)pyrrolidinyl-oxo,C(═S)N(H)(CH₂C(═O)N(H)(CH₂CF₃)), C(═S)N(H)(CH₂C(═S)N(H)(CH₂CF₃)),C(═S)N(H)(CH₂-chloropyridinyl), CH₂N(CH₂-pyridinyl)(C(═O)-cyclopropyl),CH₂N(H)(C(═O)C(═O)N(H)(CH₂CF₃), CH₂N(H)(C(═O)C(═O)OCH₃),CH₂N(H)(C(═O)C(CH₃)₃), CH₂N(H)(C(═O)—CH₂-chloropyridinyl),CH₂N(H)(C(═O)CH₂CF₃), CH₂N(H)(C(═O)CH₂CH₂S(O)₂CH₃),CH₂N(H)(C(═O)CH₂CH₂SCH₃), CH₂N(H)(C(═O)CH₂CH₃),CH₂N(H)(C(═O)-cyclopropyl), CH₂N(H)(C(═O)morpholinyl),CH₂N(H)(C(═O)N(CH₃)₂, CH₂N(H)(C(═O)N(H)(CH₂CH₃)),CH₂N(H)(C(═O)N(H)(pyridinyl)), CH₂N(H)(C(═O)OC(CH₃)₃),CH₂N(H)(C(═O)O-chlorophenyl), CH₂N(H)(C(═O)-pyridinyl),CH₂N(H)(C(═O)-chloropyridinyl), CH₂N(H)(C(═S)cyclopropyl),CH₂N(H)(C(═S)N(H)(CH₂CH═CH₂)), CH₂N(H)(C(═S)N(H)(CH₂CH₃)),CH₂N(H)(pyridinyl), N(H)(N(H)(C(═O)CH₂CF₃), N(H)(N(H)(C(═O)cyclopropyl),ON(H)(C(═O)CH₂CF₃), and ON(H)(C(═O)cyclopropyl).

In another embodiment of this invention R12 may be selected from anycombination of one or more of the following—H, F, Cl, Br, I, methyl,ethyl, (C₃)alkyl, (C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl, (C₈)alkyl,halomethyl, haloethyl, halo(C₃)alkyl, halo(C₄)alkyl, halo(C₅)alkyl,halo(C₆)alkyl, halo(C₇)alkyl, halo(C₈)alkyl, halomethoxy, haloethoxy,halo(C₃)alkoxy, halo(C₄)alkoxy, halo(C₅)alkoxy, halo(C₆)alkoxy,halo(C₇)alkoxy, and halo(C₈)alkoxy.

In another embodiment of this invention R12 is selected from CH3, and H.

In another embodiment of this invention R13 may be selected from anycombination of one or more of the following—H, F, Cl, Br, I, methyl,ethyl, (C₃)alkyl, (C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl, (C₈)alkyl,halomethyl, haloethyl, halo(C₃)alkyl, halo(C₄)alkyl, halo(C₅)alkyl,halo(C₆)alkyl, halo(C₇)alkyl, halo(C₈)alkyl, halomethoxy, haloethoxy,halo(C₃)alkoxy, halo(C₄)alkoxy, halo(C₅)alkoxy, halo(C₆)alkoxy,halo(C₇)alkoxy, and halo(C₈)alkoxy.

In another embodiment of this invention R13 is selected from CH₃, Cl andH.

In another embodiment of this invention R12-R13 are a hydrocarbyllinkage containing CH═CHCH═CH.

In another embodiment of this invention R14 may be selected from anycombination of one or more of the following—H, methyl, ethyl, (C₃)alkyl,(C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl, (C₈)alkyl, halomethyl,haloethyl, halo(C₃)alkyl, halo(C₄)alkyl, halo(C₅)alkyl, halo(C₆)alkyl,halo(C₇)alkyl, halo(C₈)alkyl, methyl-aryl, ethyl-aryl, (C₃)alkyl-aryl,(C₄)alkyl-aryl, (C₅)alkyl-aryl, (C₆)alkyl-aryl, (C₇)alkyl-aryl,(C₈)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl),(C₃)alkyl-(substituted-aryl), (C₄)alkyl-(substituted-aryl),(C₅)alkyl-(substituted-aryl), (C₆)alkyl-(substituted-aryl),(C₇)alkyl-(substituted-aryl), (C₈)alkyl-(substituted-aryl),O-methyl-aryl, O-ethyl-aryl, O—(C₃)alkyl-aryl, O—(C₄)alkyl-aryl,O—(C₅)alkyl-aryl, O—(C₆)alkyl-aryl, O—(C₇)alkyl-aryl, O—(C₈)alkyl-aryl,O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl),O—(C₃)alkyl-(substituted-aryl), O—(C₄)alkyl-(substituted-aryl),O—(C₅)alkyl-(substituted-aryl), O—(C₆)alkyl-(substituted-aryl),O—(C₇)alkyl-(substituted-aryl), O—(C₈)alkyl-(substituted-aryl),methyl-heterocyclyl, ethyl-heterocyclyl, (C₃)alkyl-heterocyclyl,(C₄)alkyl-heterocyclyl, (C₅)alkyl-heterocyclyl, (C₆)alkyl-heterocyclyl,(C₇)alkyl-heterocyclyl, (C₈)alkyl-heterocyclyl,methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl),(C₃)alkyl-(substituted-heterocyclyl),(C₄)alkyl-(substituted-heterocyclyl),(C₅)alkyl-(substituted-heterocyclyl),(C₆)alkyl-(substituted-heterocyclyl),(C₇)alkyl-(substituted-heterocyclyl),(C₈)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl,O-ethyl-heterocyclyl, O—(C₃)alkyl-heterocyclyl,O—(C₄)alkyl-heterocyclyl, O—(C₅)alkyl-heterocyclyl,O—(C₆)alkyl-heterocyclyl, O—(C₇)alkyl-heterocyclyl,O—(C₈)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl),O-ethyl-(substituted-heterocyclyl),O—(C₃)alkyl-(substituted-heterocyclyl),O—(C₄)alkyl-(substituted-heterocyclyl),O—(C₅)alkyl-(substituted-heterocyclyl),O—(C₆)alkyl-(substituted-heterocyclyl),O—(C₇)alkyl-(substituted-heterocyclyl),O—(C₈)alkyl-(substituted-heterocyclyl), methyl-C(═O)N(R16)(R17),ethyl-C(═O)N(R16)(R17), (C₃)alkyl-C(═O)N(R16)(R17),(C₄)alkyl-C(═O)N(R16)(R17), (C₅)alkyl-C(═O)N(R16)(R17),(C₆)alkyl-C(═O)N(R16)(R17), (C₇)alkyl-C(═O)N(R16)(R17), and(C₈)alkyl-C(═O)N(R16)(R17).

In another embodiment of this invention R14 may be selected from anycombination of one or more of the following—H, CH₃, CH₂CF₃,CH₂-halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH₂-phenyl,CH₂-pyridyl, thietanyl-dioxide, CH₂-halothiazolyl, C((CH₃)₂)-pyridyl,N(H)(halophenyl), CH₂-pyrimidinyl, CH₂-tetrahydrofuranyl, CH₂-furanyl,O—CH₂-halopyridyl, and CH₂C(═O)N(H)(CH₂CF₃).

In another embodiment of this invention R15 may be selected from anycombination of one or more of the following—H, methyl, ethyl, (C₃)alkyl,(C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl, (C₈)alkyl, halomethyl,haloethyl, halo(C₃)alkyl, halo(C₄)alkyl, halo(C₅)alkyl, halo(C₆)alkyl,halo(C₇)alkyl, halo(C₈)alkyl, methyl-aryl, ethyl-aryl, (C₃)alkyl-aryl,(C₄)alkyl-aryl, (C₅)alkyl-aryl, (C₆)alkyl-aryl, (C₇)alkyl-aryl,(C₈)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl),(C₃)alkyl-(substituted-aryl), (C₄)alkyl-(substituted-aryl),(C₅)alkyl-(substituted-aryl), (C₆)alkyl-(substituted-aryl),(C₇)alkyl-(substituted-aryl), (C₈)alkyl-(substituted-aryl),O-methyl-aryl, O-ethyl-aryl, O—(C₃)alkyl-aryl, O—(C₄)alkyl-aryl,O—(C₅)alkyl-aryl, O—(C₆)alkyl-aryl, O—(C₇)alkyl-aryl, O—(C₈)alkyl-aryl,O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl),O—(C₃)alkyl-(substituted-aryl), O—(C₄)alkyl-(substituted-aryl),O—(C₅)alkyl-(substituted-aryl), O—(C₆)alkyl-(substituted-aryl),O—(C₇)alkyl-(substituted-aryl), O—(C₈)alkyl-(substituted-aryl),methyl-heterocyclyl, ethyl-heterocyclyl, (C₃)alkyl-heterocyclyl,(C₄)alkyl-heterocyclyl, (C₅)alkyl-heterocyclyl, (C₆)alkyl-heterocyclyl,(C₇)alkyl-heterocyclyl, (C₈)alkyl-heterocyclyl,methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl),(C₃)alkyl-(substituted-heterocyclyl),(C₄)alkyl-(substituted-heterocyclyl),(C₅)alkyl-(substituted-heterocyclyl),(C₆)alkyl-(substituted-heterocyclyl),(C₇)alkyl-(substituted-heterocyclyl),(C₈)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl,O-ethyl-heterocyclyl, O—(C₃)alkyl-heterocyclyl,O—(C₄)alkyl-heterocyclyl, O—(C₅)alkyl-heterocyclyl,O—(C₆)alkyl-heterocyclyl, O—(C₇)alkyl-heterocyclyl,O—(C₈)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl),O-ethyl-(substituted-heterocyclyl),O—(C₃)alkyl-(substituted-heterocyclyl),O—(C₄)alkyl-(substituted-heterocyclyl),O—(C₅)alkyl-(substituted-heterocyclyl),O—(C₆)alkyl-(substituted-heterocyclyl),O—(C₇)alkyl-(substituted-heterocyclyl),O—(C₈)alkyl-(substituted-heterocyclyl), methyl-C(═O)N(R16)(R17),ethyl-C(═O)N(R16)(R17), (C₃)alkyl-C(═O)N(R16)(R17),(C₄)alkyl-C(═O)N(R16)(R17), (C₅)alkyl-C(═O)N(R16)(R17),(C₆)alkyl-C(═O)N(R16)(R17), (C₇)alkyl-C(═O)N(R16)(R17), and(C₈)alkyl-C(═O)N(R16)(R17).

In another embodiment of this invention R15 may be selected from anycombination of one or more of the following—H, CH₃, CH₂CF₃,CH₂-halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH₂-phenyl,CH₂-pyridyl, thietanyl-dioxide, CH₂-halothiazolyl, C((CH₃)₂)-pyridyl,N(H)(halophenyl), CH₂-pyrimidinyl, CH₂-tetrahydrofuranyl, CH₂-furanyl,O—CH₂-halopyridyl, and CH₂C(═O)N(H)(CH₂CF₃).

In another embodiment of this invention R16 may be selected from anycombination of one or more of the following—H, methyl, ethyl, (C₃)alkyl,(C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl, (C₈)alkyl, halomethyl,haloethyl, halo(C₃)alkyl, halo(C₄)alkyl, halo(C₅)alkyl, halo(C₆)alkyl,halo(C₇)alkyl, halo(C₈)alkyl, methyl-aryl, ethyl-aryl, (C₃)alkyl-aryl,(C₄)alkyl-aryl, (C₅)alkyl-aryl, (C₆)alkyl-aryl, (C₇)alkyl-aryl,(C₈)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl),(C₃)alkyl-(substituted-aryl), (C₄)alkyl-(substituted-aryl),(C₅)alkyl-(substituted-aryl), (C₆)alkyl-(substituted-aryl),(C₇)alkyl-(substituted-aryl), (C₈)alkyl-(substituted-aryl),O-methyl-aryl, O-ethyl-aryl, O—(C₃)alkyl-aryl, O—(C₄)alkyl-aryl,O—(C₅)alkyl-aryl, O—(C₆)alkyl-aryl, O—(C₇)alkyl-aryl, O—(C₈)alkyl-aryl,O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl),O—(C₃)alkyl-(substituted-aryl), O—(C₄)alkyl-(substituted-aryl),O—(C₅)alkyl-(substituted-aryl), O—(C₆)alkyl-(substituted-aryl),O—(C₇)alkyl-(substituted-aryl), O—(C₈)alkyl-(substituted-aryl),methyl-heterocyclyl, ethyl-heterocyclyl, (C₃)alkyl-heterocyclyl,(C₄)alkyl-heterocyclyl, (C₅)alkyl-heterocyclyl, (C₆)alkyl-heterocyclyl,(C₇)alkyl-heterocyclyl, (C₈)alkyl-heterocyclyl,methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl),(C₃)alkyl-(substituted-heterocyclyl),(C₄)alkyl-(substituted-heterocyclyl),(C₅)alkyl-(substituted-heterocyclyl),(C₆)alkyl-(substituted-heterocyclyl),(C₇)alkyl-(substituted-heterocyclyl),(C₈)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl,O-ethyl-heterocyclyl, O—(C₃)alkyl-heterocyclyl,O—(C₄)alkyl-heterocyclyl, O—(C₅)alkyl-heterocyclyl,O—(C₆)alkyl-heterocyclyl, O—(C₇)alkyl-heterocyclyl,O—(C₈)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl),O-ethyl-(substituted-heterocyclyl),O—(C₃)alkyl-(substituted-heterocyclyl),O—(C₄)alkyl-(substituted-heterocyclyl),O—(C₅)alkyl-(substituted-heterocyclyl),O—(C₆)alkyl-(substituted-heterocyclyl),O—(C₇)alkyl-(substituted-heterocyclyl), andO—(C₈)alkyl-(substituted-heterocyclyl).

In another embodiment of this invention R16 may be selected from anycombination of one or more of the following—H, CH₂CF₃, cyclopropyl,thietanyl, thietanyl dioxide, and halophenyl.

In another embodiment of this invention R17 may be selected from anycombination of one or more of the following—H, methyl, ethyl, (C₃)alkyl,(C₄)alkyl, (C₅)alkyl, (C₆)alkyl, (C₇)alkyl, (C₈)alkyl, halomethyl,haloethyl, halo(C₃)alkyl, halo(C₄)alkyl, halo(C₅)alkyl, halo(C₆)alkyl,halo(C₇)alkyl, halo(C₈)alkyl, methyl-aryl, ethyl-aryl, (C₃)alkyl-aryl,(C₄)alkyl-aryl, (C₅)alkyl-aryl, (C₆)alkyl-aryl, (C₇)alkyl-aryl,(C₈)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl),(C₃)alkyl-(substituted-aryl), (C₄)alkyl-(substituted-aryl),(C₅)alkyl-(substituted-aryl), (C₆)alkyl-(substituted-aryl),(C₇)alkyl-(substituted-aryl), (C₈)alkyl-(substituted-aryl),O-methyl-aryl, O-ethyl-aryl, O—(C₃)alkyl-aryl, O—(C₄)alkyl-aryl,O—(C₅)alkyl-aryl, O—(C₆)alkyl-aryl, O—(C₇)alkyl-aryl, O—(C₈)alkyl-aryl,O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl),O—(C₃)alkyl-(substituted-aryl), O—(C₄)alkyl-(substituted-aryl),O—(C₅)alkyl-(substituted-aryl), O—(C₆)alkyl-(substituted-aryl),O—(C₇)alkyl-(substituted-aryl), O—(C₈)alkyl-(substituted-aryl),methyl-heterocyclyl, ethyl-heterocyclyl, (C₃)alkyl-heterocyclyl,(C₄)alkyl-heterocyclyl, (C₅)alkyl-heterocyclyl, (C₆)alkyl-heterocyclyl,(C₇)alkyl-heterocyclyl, (C₈)alkyl-heterocyclyl,methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl),(C₃)alkyl-(substituted-heterocyclyl),(C₄)alkyl-(substituted-heterocyclyl),(C₅)alkyl-(substituted-heterocyclyl),(C₆)alkyl-(substituted-heterocyclyl),(C₇)alkyl-(substituted-heterocyclyl),(C₈)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl,O-ethyl-heterocyclyl, O—(C₃)alkyl-heterocyclyl,O—(C₄)alkyl-heterocyclyl, O—(C₅)alkyl-heterocyclyl,O—(C₆)alkyl-heterocyclyl, O—(C₇)alkyl-heterocyclyl,O—(C₈)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl),O-ethyl-(substituted-heterocyclyl),O—(C₃)alkyl-(substituted-heterocyclyl),O—(C₄)alkyl-(substituted-heterocyclyl),O—(C₅)alkyl-(substituted-heterocyclyl),O—(C₆)alkyl-(substituted-heterocyclyl),O—(C₇)alkyl-(substituted-heterocyclyl), andO—(C₈)alkyl-(substituted-heterocyclyl).

In another embodiment of this invention R17 may be selected from anycombination of one or more of the following—H, CH₂CF₃, cyclopropyl,thietanyl, thietanyl dioxide, and halophenyl.

In another embodiment of this invention X1 is CR12, X2 is CR13, and X3is CR9.

In another embodiment of this invention when R10 and R11 form a linkagesaid linkage is selected from (a)-(l).

In another embodiment of this invention a heterocyclyl has preferablyabout 6 to 10 atoms in the ring structure, more preferably, 6 to 8atoms.

The molecules of Formula One will generally have a molecular mass ofabout 100 Daltons to about 1200 Daltons. However, it is generallypreferred if the molecular mass is from about 120 Daltons to about 900Daltons, and it is even more generally preferred if the molecular massis from about 140 Daltons to about 600 Daltons.

The benzyl alcohol of Formula IV, wherein R1, R2, R3, R4, R5, R6, and R7are as previously disclosed, can be synthesized in two ways. One way,disclosed in step a of Scheme I, is by treatment of the ketone ofFormula II, wherein R1, R2, R3, R4, R5, and R6 are as previouslydisclosed, with a reducing agent, such as sodium borohydride (NaBH₄),under basic conditions, such as aqueous sodium hydroxide (NaOH), in apolar protic solvent, such as methyl alcohol (CH₃OH) at 0° C.Alternatively, an aldehyde of Formula III, wherein R1, R2, R3, R4, R5,and R7 are as previously disclosed, is allowed to react withtrifluorotrimethylsilane in the presence of a catalytic amount oftetrabutylammonium fluoride in a polar aprotic solvent, such astetrahydrofuran (THF), as in step b of Scheme I. The compound of FormulaIV can be transformed into the compound of Formula V, wherein Y isselected from Br, Cl or I, and R1, R2, R3, R4, R5, R6, and R7 are aspreviously disclosed, by reaction with a halogenating reagent, such asN-bromosuccinimide and triethyl phosphite in a non-reactive solvent,such as dichloromethane (CH₂Cl₂) at reflux temperature to provide Y=Br,or such as thionyl chloride and pyridine in a hydrocarbon solvent, suchas toluene at reflux temperature to provide Y=Cl, as in step c of SchemeI.

Formation of the styrene coupling partners can be accomplished as inSchemes II, III IV and V.

In Scheme II, a vinylbenzoic acid of Formula VI, wherein R11 is (C═O)OHand R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed,can be converted in two steps to the vinylbenzamide of Formula VIIa,wherein R11 is (C═O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15,and X are as previously disclosed. As in step d of Scheme II, thebenzoic acid of Formula VI is treated with oxalyl chloride in thepresence of a catalytic amount of N,N-dimethylformamide (DMF) in anon-reactive solvent such as CH₂Cl₂ to form the acid chloride, which issubsequently allowed to react with an amine (HN(R14)(R15)), wherein R14and R15 are as previously disclosed, in the presence of a base, such astriethylamine, in a polar aprotic solvent, such as THF, to provide thevinyl benzamide of Formula VIIa, wherein R11 is (C═O)N(R14)(R15), andR8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previouslydisclosed, as in step e of Scheme II.

In Schemes III and IV, a halobenzoic acid of Formula VIII, wherein R18is Br or I, R11 is (C═O)OH and R9, R10, R12, R13, X1, X2, and X3 are aspreviously disclosed can be converted to a vinylbenzoic acid ester ofFormula VIIb1 or Formula VIIb2, wherein R18 is Br or I, R11 is(C═O)O(C₁-C₆ alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are aspreviously disclosed. In step f of Scheme III, the halobenzoic acid ofFormula VIII, wherein R18 is Br, is treated with a base, such asn-butyllithium (n-BuLi), and DMF in a polar, aprotic solvent, such asTHF, at a temperature of about −78° C. The resulting formyl benzoic acidis allowed to react with an acid, such as sulfuric acid (H₂SO₄), in thepresence of an alcohol, such as ethyl alcohol (EtOH), as in step g, toprovide the formyl benzoic acid ethyl ester of Formula IX, wherein R11is (C═O)O(C₁-C₆ alkyl), and R9, R10, R12, R13, X1, X2, and X3 are aspreviously disclosed. The vinyl benzoic acid ester of Formula VIIb1 isaccessed via reaction of the compounds of Formula IX, with a base, suchas potassium carbonate (K₂CO₃), and methyl triphenyl phosphonium bromidein a polar aprotic solvent, such as 1,4-dioxane, at ambient temperature,as in step h of Scheme III.

In step i of Scheme IV, the halobenzoic acid of Formula VIII, whereinR18 is Br, R11 is (C═O)OH, and R8, R9, R10, R12, R13, X1, X2, and X3 areas previously disclosed, is treated with di-tert-butyl dicarbonate inthe presence of a base, such as triethylamine (Et₃N) and a catalyticamount of 4-(dimethylamino)pyridine (DMAP) in a polar aprotic solvent,such as THF, at ambient temperature. The resulting benzoic acidtert-butyl ester is allowed to react with vinyl boronic anhydridepyridine complex in the presence of a palladium catalyst, such atetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄), and a base, suchas K₂CO₃, in a non-reactive solvent such as toluene at refluxtemperature, as in step j, to provide the vinyl benzoic acid ester ofFormula VIIb2, wherein R11 is (C═O)O(C₁-C₆ alkyl), and R8, R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed.

In step k of Scheme V, the vinyl benzoic acid ester of Formula VIIb2,wherein R10 is Br, R11 is (C═O)O(C₁-C₆ alkyl), and R8, R9, R12, R13, X1,X2, and X3 are as previously defined, can be further transformed intothe corresponding vinyl benzoic acid ester of Formula VIIb3, wherein R10is CN, R11 is (C═O)O(C₁-C₆ alkyl), and R8, R9, R12, R13, X1, X2, and X3are as previously disclosed, by reaction with copper(I) cyanide (CuCN)in a polar aprotic solvent, such as DMF, at 140° C.

Coupling of the compounds of Formula V with the compounds of FormulaVIIa, VIIb1, VIIb2 and VIIb3 can be accomplished as in Schemes VI, VII,and VIII. In step 1 of Scheme VI, a compound of Formula V, wherein Y,R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and thevinylbenzamide of Formula VIIa, wherein R11 is (C═O)N(R14)(R15), and R8,R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed,are allowed to react in the presence of copper(I) chloride (CuCl) and2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at atemperature of about 180° C. to provide the molecules of Formula One,wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9,R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.

In step l of Scheme VII, the compound of Formula V, wherein Y, R1, R2,R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoicacid ester of Formula VIIb1, wherein R11 is (C═O)O(C₁-C₆ alkyl), and R8,R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, areallowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent,such as 1,2-dichlorobenzene, at a temperature of about 180° C. toprovide the compounds of Formula Xa, wherein R11 is (C═O)O(C₁-C₆ alkyl),and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3are as previously disclosed. The compounds of Formula Xa are thenconverted to the molecules of Formula One, wherein R11 is(C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13,R14, R15, X1, X2, and X3 are as previously disclosed, by either atwo-step process as disclosed in steps m and n or in one step asdisclosed in step o. In step m of Scheme VII, the ester of Formula Xa issaponified to the corresponding acid under acidic conditions, such asabout 11 Normal (N) hydrochloric acid (HCl), in a polar aprotic solvent,such as 1,4-dioxane, at about 100° C. The acid is subsequently coupledto an amine (HN(R14)(R15)), wherein R14 and R15 are as previouslydisclosed, with 1-hydroxybenzotriazole hydrate (HOBt.H₂O) andN-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl)in the presence of a base, such as N,N-diisopropylethylamine (DIEA), andin a polar aprotic solvent, such as DMF, to give the molecules ofFormula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5,R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are aspreviously disclosed. Alternatively, the ester of Formula Xa is allowedto react with an amine (HN(R14)(R15)) in the presence of a solution oftrimethylaluminum in toluene in a non-reactive solvent, such as CH₂Cl₂,at ambient temperature, as in step o of Scheme VII, to access themolecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2,R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 areas previously disclosed.

In step l of Scheme VIII, the compound of Formula V, wherein Y, R1, R2,R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoicacid ester of Formula VIIb2 or VIIb3, wherein R11 is (C═O)O(C₁-C₆alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previouslydisclosed, are allowed to react in the presence of CuCl and2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at atemperature of about 180° C. to provide the compounds of Formula Xb,wherein R11 is (C═O)OH, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10,R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed. Thecompounds of Formula Xb are then converted to the molecules of FormulaOne, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7,R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previouslydisclosed, in one step as disclosed in step n. In step n of Scheme VII,the acid of Formula Xb is coupled to an amine (HN(R14)(R15)), whereinR14 and R15 are as previously disclosed, with HOBt.H₂O and EDC.HCl inthe presence of a base, such as DIEA, and in a polar aprotic solvent,such as DMF, to give the molecules of Formula One, wherein R11 is(C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13,R14, R15, X1, X2, and X3 are as previously disclosed.

In step j of Scheme IX, the halobenzoketone of Formula VIIIb, whereinR18 is Br, R10 and R11 together form a linkage, having 3-4 carbon atomsand an oxo substituent and with the ring carbon atoms form a 5- or6-membered cyclic ring, and R8, R9, R12, R13, X1, X2, and X3 are aspreviously disclosed, is allowed to react with vinyl boronic anhydridepyridine complex in the presence of a palladium catalyst, such asPd(PPh₃)₄, and a base, such as K₂CO₃, in a non-reactive solvent such astoluene at reflux temperature, to provide the vinyl benzoketone ofFormula VIIb4, wherein R10 and R11 together form a linkage, having 3-4carbon atoms and an oxo substituent and with the ring carbon atoms forma 5- or 6-membered ring, and R8, R9, R12, R13, X1, X2, and X3 are aspreviously disclosed.

In step l of Scheme X, the compound of Formula V, wherein Y, R1, R2, R3,R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoketoneof Formula VIIb4 as previously disclosed, wherein R8, R9, R12, R13, X1,X2, and X3 are as previously disclosed, are allowed to react in thepresence of CuCl and 2,2-bipyridyl in a solvent, such as1,2-dichlorobenzene, at a temperature of about 180° C. to provide thecompounds of Formula Xc, wherein R10 and R11 together form a linkage,having 3-4 carbon atoms and an oxo substituent and with the ring carbonatoms form a 5- or 6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8,R9, R12, R13, X1, X2, and X3 are as previously disclosed. The compoundsof Formula Xc are then converted to the molecules of Formula Xd, whereinR10 and R11 together form a linkage, having 3-4 carbon atoms and anoxime [(C═N)(OH)] substituent and with the ring carbon atoms form a 5-or 6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13,X1, X2, and X3 are as previously disclosed, in step p. In step p ofScheme X, the ketone of Formula Xc is allowed to react withhydroxylamine hydrochloride in the presence of sodium acetate and in apolar protic solvent, such as EtOH, at a temperature of about 78° C., togive the molecules of Formula Xd as previously disclosed.

The compounds of Formula Xc are also converted to the molecules ofFormula Xe, wherein R10 and R11 together form a linkage, having 3-4carbon atoms and an amine substituent and with the ring carbon atomsform a 5- or 6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9,R12, R13, X1, X2, and X3 are as previously disclosed, as demonstrated instep q of Scheme XI. The ketone of Formula Xc is allowed to react withammonium acetate in the presence of sodium cyanoborohydride and in apolar protic solvent, such as CH₃OH, at a temperature of about 65° C.,to give the molecules of Formula Xe.

The compounds of Formula Xe are converted to the molecules of FormulaOne, wherein R10 and R11 together form a linkage as previously disclosedin (u), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3are as previously, in one step as disclosed in steps r or s. In step rof Scheme XII, the amine of Formula Xe is allowed to react with anisocyanate in a polar, aprotic solvent such as diethyl ether at ambienttemperature to provide the molecules of Formula One as previouslydisclosed. In step s of Scheme XII, the amine of Formula Xe is coupledto an acid with HOBt.H₂O and EDC.HCl in the presence of a base, such asDIEA, in a non-reactive solvent, such as CH₂Cl₂, to give the moleculesof Formula One, as previously disclosed.

In step t of Scheme XIII, the vinyl benzyl chloride of Formula XIa,wherein R11 is —CH₂Cl and R8, R9, R10, R12, R13, X1, X2, and X3 are aspreviously defined, can be transformed into the correspondingphthalimide-protected benzyl amine of Formula XIIa, wherein R11 isCH₂N(Phthalimide), and R8, R9, R10, R12, R13, X1, X2, and X3 are aspreviously disclosed, by reaction with potassium phthalimide in a polaraprotic solvent, such as DMF, at 70° C.

In step u of Scheme XIV, the 4-methylbenzonitrile of Formula XIIIa,wherein R11 is CH₃ and R9, R10, R12, R13, X1, X2, and X3 are aspreviously defined, can be transformed into the corresponding benzylbromide of Formula XIVa, wherein R11 is CH₂Br and R8, R9, R10, R12, R13,X1, X2, and X3 are as previously disclosed, by reaction withN-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in anon-reactive solvent, such as carbon tetrachloride at 77° C. The nitrilegroup (CN) of Formula XIVa can be reduced to the corresponding aldehydeof Formula XVa, wherein R11 is CH₂Br and R9, R10, R12, R13, X1, X2, andX3 are as previously defined via reaction with diisobutylaluminumhydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0° C.,followed by quenching with 1.0 M hydrochloric acid (HCl) as in step v ofScheme XIV. The compound of Formula XVa can be further transformed tothe corresponding phthalimide-protected benzyl amine of Formula XVIa,wherein R11 is CH₂N(Phthalimide) and R9, R10, R12, R13, X1, X2, and X3are as previously disclosed, by reaction with potassium phthalimide in apolar aprotic solvent, such as DMF, at 60° C. as in step t of SchemeXIV. In step w of Scheme XIV, the aldehyde of Formula XVIa can beconverted to the olefin of Formula XIIb, wherein R11 isCH₂N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are aspreviously disclosed, by reaction with methyl triphenyl phosphoniumbromide in a polar aprotic solvent, such as 1,4-dioxane, in the presenceof a base, such as K₂CO₃, at ambient temperature.

The aldehyde of Formula XVa, wherein R11 is CH₂Br and R9, R10, R12, R13,X1, X2, and X3 are as previously defined, can be reacted with anucleophile, such as 2-aminopyridine, in a polar aprotic solvent, suchas N,N-dimethylacetamide (DMA), in the presence of a base, such asK₂CO₃, at ambient temperature to provide the compound of Formula XVII,wherein R11 is CH₂NH(2-pyridine) and R9, R10, R12, R13, X1, X2, and X3are as previously disclosed, as in step x of Scheme XV. In step w ofScheme XV, the compound of Formula XVII can be converted to the olefinof Formula XVIII, wherein R11 is CH₂NH(2-pyridine) and R8, R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed.

In a two-step, one-pot reaction as in steps y and z of Scheme XVI, thecompound of Formula XIX can be reacted with the compounds of Formula XX,wherein R10 and R11 are Cl, X1 is N, and R9, R13, X2, and X3 are aspreviously disclosed, in the presence of a base, such as sodium hydride(NaH), and a polar aprotic solvent, such as DMF, at ambient temperatureto provide the compounds of Formula XXI, wherein R10 is Cl, R11 is(CH)NH₂CO₂CH₂CH₃, X1 is N, and R9, R13, X2, and X3 are as previouslydefined. Hydrolysis and decarboxylation of the compounds of Formula XXIcan be accomplished by reaction under acidic conditions, such as with 3N HCl, at reflux temperature, to afford the compounds of Formula XXII,wherein R10 is Cl, R11 is CH₂NH₂.HCl, X1 is N, and R9, R13, X2, and X3are as previously disclosed, as in step aa in Scheme XVI. The compoundsof Formula XXII can be further transformed to the correspondingphthalimide-protected benzyl amines of Formula XXIIIa, wherein R10 isCl, R11 is CH₂N(Phthalimide), X1 is N, and R9, R13, X1, X2, and X3 areas previously disclosed, by reaction with phthalic anhydride in thepresence of a base, such as Et₃N, and an aprotic solvent, such astoluene, at reflux temperature as in step ab of Scheme XVI. The bromideof Formula XXIIIa can be converted to the olefin of Formula XIIc,wherein R10 is Cl, R11 is CH₂N(Phthalimide), X1 is N, and R8, R9, R13,X2 and X3 are as previously disclosed, by reaction with vinyl boronicanhydride pyridine complex in the presence of a palladium catalyst, suchas Pd(PPh₃)₄, and a base, such as K₂CO₃, in a non-reactive solvent suchas toluene at reflux temperature, as in step ac of Scheme XVI.

In step u of Scheme XVII, the 4-methylnaphthonitrile of Formula XIIIb,wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbonatoms and with the ring carbon atoms form a 6-membered aromatic ring,R11 is CH₃, and R12, R13, X1 and X2 are as previously defined, can betransformed into the corresponding naphthyl bromide of Formula XIVb,wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbonatoms and with the ring carbon atoms form a 6-membered aromatic ring,R11 is CH₂Br, and R12, R13, X1 and X2 are as previously disclosed, byreaction with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN)in a non-reactive solvent, such as carbon tetrachloride at 77° C. Thenitrile group (CN) of Formula XIVb can be reduced to the correspondingaldehyde of Formula XVb, wherein X3 is CR9, R10 and X3 together form alinkage having 4 carbon atoms and with the ring carbon atoms form a6-membered aromatic ring (or if desired a non-aromatic ring), R11 isCH₂Br, and R12, R13, X1 and X2 are as previously defined via reactionwith diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such astoluene, at 0° C., followed by quenching with 1.0 M HCl as in step v ofScheme XVII. The compound of Formula XVb can be further transformed tothe corresponding phthalimide-protected benzyl amine of Formula XVIb,wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbonatoms and with the ring carbon atoms form a 6-membered aromatic ring,R11 is CH₂N(Phthalimide), and R12, R13, X1 and X2 are as previouslydisclosed, by reaction with potassium phthalimide in a polar aproticsolvent, such as DMF, at 60° C. as in step t of Scheme XVII. In step wof Scheme XVII, the aldehyde of Formula XVIb can be converted to theolefin of Formula XIId, wherein X3 is CR9, R10 and X3 together form alinkage having 4 carbon atoms and with the ring carbon atoms form a6-membered aromatic ring, R11 is CH₂N(Phthalimide), and R8, R12, R13, X1and X2 are as previously disclosed, by reaction with methyl triphenylphosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, inthe presence of a base, such as K₂CO₃, at ambient temperature.

The compound of Formula XXIV, wherein R11 is NHNH₂.HCl and R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed, can be transformed intothe corresponding phthalimide-protected hydrazine of Formula XXV,wherein R11 is NHN(Phthalimide) and R9, R10, R12, R13, X1, X2, and X3are as previously disclosed, by reaction with phthalic anhydride inglacial acetic acid at reflux temperature as in step ad of Scheme XVIII.The bromide of Formula XXV can be converted to the olefin of FormulaXIIe, wherein R11 is NHN(Phthalimide) and R8, R9, R10, R13, X1, X2 andX3 are as previously disclosed, by reaction with vinyl boronic anhydridepyridine complex in the presence of a palladium catalyst, such asPd(PPh₃)₄, and a base, such as K₂CO₃, in a polar aprotic solvent such as1,2-dimethoxyethane at 150° C. under microwave conditions, as in step aeof Scheme XVIII.

In step of af Scheme XIX, the compound of Formula XXVI, wherein R11 isB(OH)₂, and R8, R9, R10, R12, R13, X1, X2, and X3 are as previouslydisclosed, are allowed to react with 2-hydroxyisoindoline-1,3-dione inthe presence of CuCl and pyridine in a solvent, such as1,2-dichlorobenzene, at ambient temperature to provide the compound ofFormula XIIf, wherein R11 is ON(Phthalimide) and R8, R9, R10, R12, R13,X1, X2, and X3 are as previously disclosed.

In step l of Scheme XX, the compound of Formula V, wherein Y, R1, R2,R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds ofFormula XIIa, wherein R11 is CH₂N(Phthalimide) and R8, R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed, are allowed to react inthe presence of CuCl and 2,2-bipyridyl in a solvent, such as1,2-dichlorobenzene, at a temperature of about 180° C. to provide thecorresponding compounds of Formula XXVIIa, wherein R11 isCH₂N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13,X1, X2, and X3 are as previously disclosed. The phthalimide protectinggroup in the compounds of Formula XXVIIa is removed as in step ag ofScheme XX by reaction with hydrazine hydrate in a polar protic solventsuch as EtOH at 90° C. to provide the compounds of Formula XXVIIIa,wherein R11 is CH₂NH₂ and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed. The compounds ofFormula XXVIIIa can be transformed into the compounds of Formula One,wherein R11 is CH₂N(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9,R10, R12, R13, X1, X2, and X3 are as previously disclosed, by acylationwith an anhydride, such as acetic anhydride, and a base, such as Et₃N,in a non-reactive solvent such as CH₂Cl₂ at 0° C. as in step ah₁ ofScheme XX.

In step l of Scheme XXI, the compound of Formula V, wherein Y, R1, R2,R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds ofFormula XIIb, wherein R11 is CH₂N(Phthalimide) and R8, R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed, are allowed to react inthe presence of CuCl and 2,2-bipyridyl in a solvent, such as1,2-dichlorobenzene, at a temperature of about 180° C. to provide thecorresponding compounds of Formula XXVIIb, wherein R11 isCH₂N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13,X1, X2, and X3 are as previously disclosed. The phthalimide protectinggroup in the compounds of Formula XXVIIb is removed as in step ag ofScheme XXI by reaction with hydrazine hydrate in a polar protic solventsuch as EtOH at 90° C. to provide the compounds of Formula XXVIIIb,wherein R11 is CH₂NH₂ and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed. The compounds ofFormula XXVIIIb can be transformed into the compounds of Formula One,wherein R11 is CH₂N(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9,R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reactionwith an acid in the presence of HOBt.H₂O, EDC.HCl and a base, such asDIEA, in a polar aprotic solvent, such as DMF, as in step ah_(a) ofScheme XXI.

In another embodiment, the compounds of Formula XXVIIIb can betransformed into the compounds of Formula One, wherein R11 isCH₂N(C═S)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13,X1, X2, and X3 are as previously disclosed, by reaction with a thioacidin the presence of HOBt.H₂O, EDC.HCl and a base, such as DIEA, in apolar aprotic solvent, such as DMF, as in step ah₂ of Scheme XXI.

In another embodiment, the compounds of Formula XXVIIIb can betransformed into the compounds of Formula One, wherein R11 isCH₂N(C═O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed, in two steps. The firststep (step ah_(3a) of Scheme XXI) involves reaction with an aldehyde ina polar protic solvent such as methyl alcohol, followed by reaction withsodium borohydride. The second step (step ah_(3b) of Scheme XXI)involves acylation with an acid chloride, such as cyclopropylcarbonylchloride, and a base, such as Et₃N, in a non-reactive solvent such asCH₂Cl₂ at ambient temperature of Scheme XXI.

In another embodiment, the compounds of Formula XXVIIIb can betransformed into the compounds of Formula One, wherein R11 isCH₂N(C═O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed, by reaction with anisocyanate (step ai₁ of Scheme XXI) or a carbamoyl chloride (step ai₂ ofScheme XXI) in the presence of a base such as Et₃N and in a non-reactivesolvent such as CH₂Cl₂ at 0° C.

In another embodiment, the compounds of Formula XXVIIIb can betransformed into the compounds of Formula One, wherein R11 isCH₂N(C═S)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed, by reaction with anisothiocyanate in the presence of a base such as Et₃N and in anon-reactive solvent such as CH₂Cl₂ at 0° C., as in steps aj of SchemeXXI.

In another embodiment, the compounds of Formula XXVIIIb can betransformed into the compounds of Formula One, wherein R11 isCH₂N(C═O)O(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13,X1, X2, and X3 are as previously disclosed, by reaction with adicarbonate, such as di-tert-butyl dicarbonate in the presence of a basesuch as Et₃N and in a non-reactive solvent such as CH₂Cl₂ at ambienttemperature, as in steps ak of Scheme XXI.

In yet another embodiment, the compounds of Formula XXVIIIb can betransformed into the compounds of Formula One, wherein R11 isCH₂N(C═O)(C═O)O(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed, by reaction with achlorooxalic acid ester, such as 2-chloro-2-oxoacetate in the presenceof a base such as Et₃N and in a non-reactive solvent such as CH₂Cl₂ at0° C., as in steps al of Scheme XXI.

In step l of Scheme XXII, the compound of Formula V, wherein Y, R1, R2,R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds ofFormula XIIc, wherein R10 is Cl, R11 is CH₂N(Phthalimide), X1 is N, andR8, R9, R12, R13, X2, and X3 are as previously disclosed, are allowed toreact in the presence of CuCl and 2,2-bipyridyl in a solvent, such as1,2-dichlorobenzene, at a temperature of about 180° C. to provide thecorresponding compounds of Formula XXVIIc, wherein R10 is Cl, R11 isCH₂N(Phthalimide), X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12,R13, X2, and X3 are as previously disclosed. The phthalimide protectinggroup in the compounds of Formula XXVIIc is removed as in step ag ofScheme XXII by reaction with hydrazine hydrate in a polar protic solventsuch as EtOH at 90° C. to provide the compounds of Formula XXVIIIc,wherein R10 is Cl, R11 is CH₂NH₂, X1 is N, and R1, R2, R3, R4, R5, R6,R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed. Thecompounds of Formula XXVIIIc can be transformed into the compounds ofFormula One, wherein R10 is Cl, R11 is CH₂N(C═O)(R14), X1 is N, and R1,R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previouslydisclosed, by reaction with an acid in the presence of HOBt.H₂O, EDC.HCland a base, such as DIEA, in a polar aprotic solvent, such as CH₂Cl₂, asin step ah_(2b) of Scheme XXII.

In step l of Scheme XXIII, the compound of Formula V, wherein Y, R1, R2,R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds ofFormula XIId, wherein X3 is CR9, R10 and X3 together form a linkagehaving 4 carbon atoms and with the ring carbon atoms form a 6-memberedaromatic ring (or if desired a non-aromatic ring), R11 isCH₂N(Phthalimide) and R8, R9, R12, R13, X1 and X2 are as previouslydisclosed, are allowed to react in the presence of CuCl and2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at atemperature of about 180° C. to provide the corresponding compounds ofFormula XXVIId, wherein X3 is CR9, R10 and X3 together form a linkagehaving 4 carbon atoms and with the ring carbon atoms form a 6-memberedaromatic ring, R11 is CH₂N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7,R8, R9, R12, R13, X1 and X2 are as previously disclosed. The phthalimideprotecting group in the compounds of Formula XXVIId is removed as instep ag of Scheme XXIII by reaction with hydrazine hydrate in a polarprotic solvent such as EtOH at 90° C. to provide the compounds ofFormula XXVIIId, wherein X3 is CR9, R10 and X3 together form a linkagehaving 4 carbon atoms and with the ring carbon atoms form a 6-memberedaromatic ring, R11 is CH₂NH₂ and R1, R2, R3, R4, R5, R6, R7, R8, R9,R12, R13, X1 and X2 are as previously disclosed. The compounds ofFormula XXVIIId can be transformed into the compounds of Formula One,wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbonatoms and with the ring carbon atoms form a 6-membered aromatic ring,R11 is CH₂N(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13,X1 and X2 are as previously disclosed, by reaction with an acid in thepresence of HOBt.H₂O, EDC.HCl and a base, such as DIEA, in a polaraprotic solvent, such as CH₂Cl₂, as in step ah_(2b) of Scheme XXIII

In another embodiment, the compounds of Formula XXVIIId can betransformed into the compounds of Formula One, wherein X3 is CR9, R10and X3 together form a linkage having 4 carbon atoms and with the ringcarbon atoms form a 6-membered aromatic ring, R11 isCH₂N(C═O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12,R13, X1 and X2 are as previously disclosed, by reaction with anisocyanate in the presence of a base such as Et₃N and in a non-reactivesolvent such as CH₂Cl₂ at 0° C. as in step ai₁ of Scheme XXIII.

In step l of Scheme XXIV, the compound of Formula V, wherein Y, R1, R2,R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds ofFormula XIIe, wherein R11 is NHN(Phthalimide) and R8, R9, R12, R13, X1,X2, and X3 are as previously disclosed, are allowed to react in thepresence of CuCl and 2,2-bipyridyl in a solvent, such as1,2-dichlorobenzene, at a temperature of about 180° C. to provide thecorresponding compounds of Formula XXVIIe, wherein R11 isNHN(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1,X2, and X3 are as previously disclosed. The phthalimide protecting groupin the compounds of Formula XXVIIe is removed as in step ag of SchemeXXIV by reaction with hydrazine hydrate in a polar protic solvent suchas EtOH at 90° C. to provide the compounds of Formula XXVIIIe, whereinR11 is NHNH₂ and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2,and X3 are as previously disclosed. The compounds of Formula XXVIIIe canbe transformed into the compounds of Formula One, wherein R11 isNHN(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2,and X3 are as previously disclosed, by reaction with an acid in thepresence of HOBt.H₂O, EDC.HCl and a base, such as DIEA, in a polaraprotic solvent, such as CH₂Cl₂, as in step ah_(2b) of Scheme XXIV.

In step l of Scheme XXV, the compound of Formula V, wherein Y, R1, R2,R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds ofFormula XIIf, wherein R11 is ON(Phthalimide) and R8, R9, R10, R12, R13,X1, X2, and X3 are as previously disclosed, are allowed to react in thepresence of CuCl and 2,2-bipyridyl in a solvent, such as1,2-dichlorobenzene, at a temperature of about 180° C. to provide thecorresponding compounds of Formula XXVIIf, wherein R11 isON(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13,X1, X2, and X3 are as previously disclosed. The phthalimide protectinggroup in the compounds of Formula XXVIIf is removed as in step ag ofScheme XXV by reaction with hydrazine hydrate in a polar protic solventsuch as EtOH at 90° C. to provide the compounds of Formula XXVIIIf,wherein R11 is ONH₂ and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed. The compounds ofFormula XXVIIIf can be transformed into the compounds of Formula One,wherein R11 is ON(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10,R12, R13, X1, X2, and X3 are as previously disclosed, by reaction withan acid in the presence of HOBt.H₂O, EDC.HCl and a base, such as DIEA,in a polar aprotic solvent, such as CH₂Cl₂, as in step ah_(2b) of SchemeXXV.

In step l of Scheme XXVI, the compound of Formula V, wherein Y, R1, R2,R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds ofFormula XVIII, wherein R11 is CH₂NH(2-pyridine) and R8, R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed, are allowed to react inthe presence of CuCl and 2,2-bipyridyl in a solvent, such as1,2-dichlorobenzene, at a temperature of about 180° C. to provide thecorresponding compounds of Formula One, wherein R11 isCH₂NH(2-pyridine), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12,R13, X1, X2, and X3 are as previously disclosed.

The compounds of Formula One can be further elaborated by standardmethods. For example, when R11 contains a thioether, the thioether canbe oxidized to the sulfone by treatment with oxone in the presence of anacetone:water mixture at ambient temperature. When R11 contains anoxalate ester, the compound of Formula One can be transformed into thecorresponding oxalamide by reaction with an amine hydrochloride and asolution of trimethylaluminum in toluene in a non-reactive solvent suchas CH₂Cl₂.

In Scheme XXVII, a fluorobenzaldehyde of Formula XXIX, wherein R10, X1,X2, and X3 are as previously disclosed can be converted to a(1,2,4-triazol-1-yl)benzaldehyde of Formula XXX, wherein R11 is asubstituted or unsubstituted 1,2,4-triazol-1-yl group, and R10, X1, X2,and X3 are as previously disclosed by reaction with a substituted orunsubstituted 1,2,4-triazole in the presence of a base, such aspotassium carbonate, in a solvent such as DMF as in step aj. In step ak,the (1,2,4-triazol-1-yl)benzaldehyde of Formula XXX is converted to a(1,2,4-triazol-1-yl)vinyl benzene of Formula XXXIa wherein R11 is asubstituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R10, X1,X2, and X3 are as previously disclosed by reaction with triphenylphosphonium bromide in the presence of a base, such as potassiumcarbonate, in an aprotic solvent, such as 1,4-dioxane.

In Scheme XXVIII, a bromofluorobenzene of Formula XXXII, wherein R10,X1, X2, and X3 are as previously disclosed can be converted to a(1,2,4-triazol-1-yl)vinylbenzene of Formula XXXIb, wherein R11 is asubstituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R10, X1,X2, and X3 are as previously disclosed in two steps. In step al, thebromofluorobenzene is reacted with a substituted or unsubstituted1,2,4-triazole in the presence of a base, such as potassium carbonate,in a solvent such as DMF to generate the(1,2,4-triazol-1-yl)bromobenzene. In step cl, the(1,2,4-triazol-1-yl)bromobenzene is reacted with vinyl boronic anhydridepyridine complex in the presence of a catalyst, such as Pd (PPh₃)₄, anda base, such as potassium carbonate in a solvent such as toluene.

Coupling of the compounds of Formula V with compounds of Formula XXXIaand XXXIb can be accomplished as in Schemes XXIX. In step l, a compoundof Formula V, wherein Y is Br, R1, R2, R3, R4, R5, R6, and R7 are aspreviously disclosed, and a vinylbenzene of Formula XXXIa or XXXIb,wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group,and R8, R9, R10, X1, X2, and X3 are as previously disclosed, are allowedto react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as1,2-dichlorobenzene, at a temperature of about 180° C. to provide themolecules of Formula One, wherein R11 is a substituted or unsubstituted1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1,X2, and X3 are as previously disclosed.

In Scheme XXX, compounds of Formula XXXIII wherein R11 is a3-nitro-1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R8,R10, X1, X2, and X3 are as previously disclosed can be converted tocompounds of Formula One, wherein R11 is a 3-amido-1,2,4-triazol-1-ylgroup, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are aspreviously disclosed by a two step process. In step am, the3-nitro-1,2,4-triazol-1-yl group is reduced to a3-amino-1,2,4-triazol-1-yl group in the presence of zinc dust andammonium chloride in a protic solvent, such as methanol. In step an, the3-amino-1,2,4-triazol-1-yl group is acylated with an acid chloride, suchas cyclopropylcarbonyl chloride or acetyl chloride, in the presence of abase, such as triethylamine, in a solvent such as dichloromethane.

In step ao of Scheme XXXI, a bromophenyl methyl ketone of Formula XXXIVwherein R10, X1, X2, and X3 are as previously disclosed is converted toan phenyl methyl ketone of the Formula XXXV wherein R11 is a1,2,4-triazol-1-yl group, and R10, X1, X2, and X3 are as previouslydisclosed by treatment with 1,2,4-triazole in the presence of a base,such as cesium carbonate, and a catalyst, such as copper iodide, in asolvent, such as DMF. In step ap, the 1,2,4-triazolylacetophenone ofFormula XXXV is converted to the trimethylsilyl enol ether of FormulaXXXVI by treatment with trimethylsilyl triflluoromethanesulfonate in thepresence of a base, such as triethylamine, in an aprotic solvent, suchas dichloromethane. In step aq, the silyl enol ether is reacted with acompound of Formula V, wherein Y is Br, R1, R2, R3, R4, R5, R6, and R7are as previously disclosed in the presence of CuCl and 2,2-bipyridyl ina solvent, such as 1,2-dichlorobenzene at a temperature of about 180° C.to generate a ketone of the Formula XXXVII, wherein R11 is a1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R10, X1, X2,and X3 are as previously disclosed. In step ar, the ketone of theFormula XXXVII is treated with methylmagnesium bromide in an aproticsolvent, such as THF to generate the tertiary alcohol. The tertiaryalcohol then undergoes an elimination reaction when treated with acatalytic amount of p-toluenesulfonic acid in a solvent, such astoluene, when heated to a temperature to allow azeotropic removal ofwater to produce compounds of Formula One wherein R11 is a1,2,4-triazol-1-yl group, R8 is methyl, and R1, R2, R3, R4, R5, R6, R7,R10, X1, X2, and X3 are as previously disclosed, as in step as.

In Scheme XXXII, a compound of Formula XXXVIII, wherein R10 and R11together form a linkage, having 3-4 carbon atoms and an oxo substituentand with the ring carbon atoms form a 5- or 6-membered cyclic ring, andR1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previouslydisclosed is converted to a molecule of Formula One, wherein R10 and R11together form a linkage, having 3-4 carbon atoms and an alkylaminesubstituent with the ring carbon atoms form a 5- or 6-membered cyclicring and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are aspreviously disclosed, by treatment with an alkylamine, such as3,3,3-trifluoropropylamine, in the presence of a reducing agent, such assodium cyanoborohydride, in a solvent, such as DCE.

In Scheme XXXIII, a compound of Formula XXXIX, wherein X1, X2, and X3are as previously disclosed is converted to a molecule of Formula XL,wherein X1, X2, and X3 are as previously disclosed, by treatment with areducing agent, such as sodium cyanoborohydride, in a solvent, such asacetic acid, as in step au. In step av, the nitrogen atom is protectedwith a tert-butyloxycarbonyl (BOC) group by reaction with di-tert-butyldicarbonate in the presence of a catalyst, such as DMAP, in a solvent,such as acetonitrile. The bromide of Formula XL can be converted to theolefin of Formula XLI, wherein R8, X1, X2 and X3 are as previouslydisclosed, by reaction with potassium vinyl trifluoroborate in thepresence of a palladium catalyst, such as PdCl₂(dppf), and a base, suchas K₂CO₃, in a polar aprotic solvent such as DMSO at 100° C., as in stepaw.

In Scheme XXXIV, a compound of Formula XXXIX, wherein X1, X2, and X3 areas previously disclosed is converted to a molecule of Formula XLII,wherein X1, X2, and X3 are as previously disclosed in two steps. In stepax, the olefin is formed by treatment of the bromide with potassiumvinyl trifluoroborate in the presence of a palladium catalyst, such asPdCl₂, and a ligand, such as triphenylphosphine, and a base, such asCs₂CO₃, in a solvent mixture such as THF/H₂O. In step ay, the nitrogenatom is protected with a tert-butyloxycarbonyl (BOC) group by reactionwith di-tert-butyl dicarbonate in the presence of a catalyst, such asDMAP, in a solvent, such as acetonitrile.

In step l of Scheme XXXV, the compound of Formula V, wherein Y, R1, R2,R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds ofFormula XLI or XLII, wherein R8, X1, X2 and X3 are as previouslydisclosed, are allowed to react in the presence of CuCl and2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at atemperature of about 150° C. to provide the corresponding compounds ofFormula XLIIIa or XLIIIb, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1,X2, and X3 are as previously disclosed.

In Scheme XXXVI, a compound of Formula XLIIIa, wherein R1, R2, R3, R4,R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed is convertedto a molecule of Formula XLIV, wherein R1, R2, R3, R4, R5, R6, R7, R8,X1, X2, and X3 are as previously disclosed by treatment withtrifluoroacetic acid, in a solvent such as dichloromethane, as in stepaz. Compounds of the Formula XLIV can then be transformed into compoundsof the Formula XLV wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, andX3 are as previously disclosed, in two steps. In step ba, the indolineis treated with sodium nitrite (NaNO₂), in an acid, such as concentratedHCl, at a temperature around 5° C., to form the nitrosoindole. In stepbb, the nitrosoindole is reacted with ammonium chloride in the presenceof zinc powder in a protic solvent, such as methanol. In step bc,compounds of the Formula XLV are transformed into compounds of theFormula XLVI, wherein X4 is N(R14)(C(═O)R14) and R1, R2, R3, R4, R5, R6,R7, R8, X1, X2, and X3 are as previously disclosed, by treatment withand acid, such as 3,3,3-trifluoropropanoic acid, PyBOP, and a base, suchas DIEA, in a polar aprotic solvent, such as dichloromethane.

In Scheme XXXVII, a compound of Formula XLIIIb, wherein R1, R2, R3, R4,R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed is convertedto an indole of Formula XLVII, wherein R1, R2, R3, R4, R5, R6, R7, R8,X1, X2, and X3 are as previously disclosed by treatment withtrifluoroacetic acid, in a solvent such as dichloromethane, as in stepbd. Compounds of the Formula XLVII can be transformed into compounds ofthe Formula XLVIII wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, andX3 are as previously disclosed, by reaction with4-nitrophenyl-2-((tert-butoxycarbonyl)amino)acetate in the presence ofpotassium fluoride and a crown ether, such as 18-crown-6-ether, in asolvent, such as acetonitrile, as in step be. Compounds of the FormulaXLVIII can be transformed into compounds of the Formula XLIX, whereinR1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previouslydisclosed in two steps. In step bf, the Boc group is removed bytreatment with trifluoroacetic acid, in a solvent such asdichloromethane. In step bg, the amine is treated with3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIEA, in apolar aprotic solvent, such as dichloromethane.

In Scheme XXXVIII, a compound of Formula L, wherein X1, X2, and X3 areas previously disclosed is converted to a compound of the Formula LI,wherein X1, X2, and X3 are as previously disclosed by treatment withcopper (II) sulfate pentahydrate and Zn powder in a base, such as sodiumhydroxide as in step bh. Compounds of the Formula LI can be transformedinto compounds of the Formula LII wherein X1, X2, and X3 are aspreviously disclosed, by reaction with hydrazine, in a solvent such aswater, at a temperature around 95° C., as in step bi. In step bj, theolefin of the Formula LIII wherein X1, X2, and X3 are as previouslydisclosed is formed by treatment of the bromide with potassium vinyltrifluoroborate in the presence of a palladium catalyst, such asPdCl₂(dppf), and a base, such as K₂CO₃, in a solvent mixture such asDMSO. Compounds of the Formula LIV, wherein X1, X2, and X3 are aspreviously disclosed, can be formed from compounds of the Formula LIIIby reaction with ethyl bromoacetate, in the presence of a base, such asCs₂CO₃, in a solvent, such as DMF.

In step l of Scheme XXXIX, the compound of Formula V, wherein Y, R1, R2,R3, R4, R5, R6, and R7 are as previously disclosed, and the compound ofFormula LIV, wherein R8, X1, X2 and X3 are as previously disclosed, areallowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent,such as 1,2-dichlorobenzene, at a temperature of about 180° C. toprovide the corresponding compound of Formula LV, wherein R1, R2, R3,R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed. Thecompound of Formula LV can be further transformed into a compound of theFormula LVI, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 areas previously disclosed, in two steps. In step bl, the ester ishydrolyzed to the acid in the presence of HCl and acetic acid, at atemperature of about 100° C. In step bm, the acid is treated with anamine, such as 2,2,2-trifluoroethylamine, PyBOP, and a base, such asDIEA, in a polar aprotic solvent, such as dichloromethane.

In step bn of Scheme XL, carboxylic acids of the Formula LVII, whereinR11 is C(═O)OH and R8, R10, X1, X2, and X3 are as previously disclosedand compounds of the Formula V, wherein Y is Br and R1, R2, R3, R4, R5,R6, and R7 are as previously disclosed are allowed to react in thepresence of CuCl and 2,2-bipyridyl in a solvent, such as N-methylpyrrolidine, at a temperature of about 150° C. to afford compounds ofFormula LVIII, wherein R11 is (C═O)OH and R1, R2, R3, R4, R5, R6, R7,R8, R9, R10, X1, X2, and X3 are as previously disclosed. Compounds ofthe Formula LVIII can be further transformed to the correspondingbenzamides of Formula LIX, wherein R11 is (C═O)N(R14)(R15), and R1, R2,R3, R4, R5, R6, R7, R8, R9, R10, X1, X2, and X3 are as previouslydisclosed, by treatment with an amine, such as2-amino-N-(2,2,2-trifluoroethyl)acetamide, PyBOP, and a base, such asDIEA, in a polar aprotic solvent, such as dichloromethane, as in stepbo.

EXAMPLES

The examples are for illustration purposes and are not to be construedas limiting the invention disclosed in this document to only theembodiments disclosed in these examples.

Starting materials, reagents, and solvents that were obtained fromcommercial sources were used without further purification. Anhydroussolvents were purchased as Sure/Seal™ from Aldrich and were used asreceived. Melting points were obtained on a Thomas Hoover Unimeltcapillary melting point apparatus or an OptiMelt Automated Melting PointSystem from Stanford Research Systems and are uncorrected. Molecules aregiven their known names, named according to naming programs within ISISDraw, ChemDraw, or ACD Name Pro. If such programs are unable to name amolecule, the molecule is named using conventional naming rules. ¹H NMRspectral data are in ppm (δ) and were recorded at 300, 400, or 600 MHz,and ¹³C NMR spectral data are in ppm (δ) and were recorded at 75, 100,or 150 MHz, unless otherwise stated.

Example 1 Preparation of1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (AI1)

Step 1 Method A. 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (AI2)

To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone(procured from Rieke Metals, UK; 5.0 grams (g), 20.5 millimoles (mmol))in methyl alcohol (CH₃OH; 100 milliliters (mL)) at 0° C. were addedsodium borohydride (NaBH₄; 3.33 g, 92.5 mL) and 1 Normal (N) aqueoussodium hydroxide solution (NaOH; 10 mL). The reaction mixture was warmedto 25° C. and stirred for 2 hours (h). After the reaction was deemedcomplete by thin layer chromatography (TLC), saturated (satd) aqueous(aq) ammonium chloride (NH₄Cl) solution was added to the reactionmixture, and the mixture was concentrated under reduced pressure. Theresidue was diluted with diethyl ether (Et₂O) and washed with water(H₂O; 3×50 mL). The organic layer was dried over sodium sulfate (Na₂SO₄)and concentrated under reduced pressure to afford the title compound asa liquid (4.0 g, 79%): ¹H NMR (400 MHz, CDCl₃) δ 7.41 (m, 3H), 5.00 (m,2H), 2.74 (s, 1H); ESIMS m/z 242.97 ([M−H]⁻).

Step 1 Method B. 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (AI2)

To a stirred solution of 3,5-dichlorobenzaldehyde (10 g, 57 mmol) intetrahydrofuran (THF; 250 mL) were added trifluoromethyltrimethylsilane(9.79 g, 69.2 mmol) and a catalytic amount of tetrabutylammoniumfluoride (TBAF). The reaction mixture was stirred at 25° C. for 8 h.After the reaction was deemed complete by TLC, the reaction mixture wasdiluted with 3 N hydrochloric acid (HCl) and then was stirred for 16 h.The reaction mixture was diluted with H₂O and was extracted with ethylacetate (EtOAc; 3×). The combined organic extracts were washed withbrine, dried over Na₂SO₄, and concentrated under reduced pressure toafford the title compound as a liquid (8.41 g, 60%).

The following compounds were made in accordance with the proceduresdisclosed in Step 1 Method B of Example 1 above.

2,2,2-Trifluoro-1-(3,4,5-trichlorophenyl)ethanol (AI3)

The product was isolated as a pale yellow liquid (500 mg, 65%): ¹H NMR(400 MHz, CDCl₃) δ 7.45 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m/z278 ([M+H]⁺); IR (thin film) 3420, 1133, 718 cm⁻¹.

1-(3,5-Dichloro-4-fluorophenyl)-2,2,2-trifluoroethanol (AI4)

The product was isolated as a pale yellow liquid (500 mg, 65%): ¹H NMR(400 MHz, CDCl₃) δ 7.41 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m/z262 ([M+H]⁺); IR (thin film) 3420, 1133, 718 cm⁻¹.

1-(3,4-Dichlorophenyl)-2,2,2-trifluoroethanol (AI5)

The product was isolated as a pale yellow liquid (500 mg, 65%): ¹H NMR(400 MHz, CDCl₃) δ 7.60 (s, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m,1H), 2.60 (s, 1H); EIMS m/z 244 ([M]⁺).

Step 2. 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (AI1)

To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanol(4.0 g, 16.3 mmol) in dichloromethane (CH₂Cl₂; 50 mL), were addedN-bromosuccinimide (NBS; 2.9 g, 16.3 mmol) and triphenyl phosphite (5.06g, 16.3 mmol), and the resultant reaction mixture was heated at refluxfor 18 h. After the reaction was deemed complete by TLC, the reactionmixture was cooled to 25° C. and was concentrated under reducedpressure. Purification by flash column chromatography (SiO₂, 100-200mesh; eluting with 100% pentane) afforded the title compound as a liquid(2.0 g, 40%): ¹H NMR (400 MHz, CDCl₃) δ 7.41 (s, 3H), 5.00 (m, 1H); EIMSm/z 306 ([M]⁺).

The following compounds were made in accordance with the proceduresdisclosed in Step 2 of Example 1.

5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (AI6)

The product was isolated as a colorless oil (300 mg, 60%): ¹H NMR (400MHz, CDCl₃) δ 7.59 (s, 2H), 5.00 (m, 1H); EIMS m/z 340.00 ([M]⁺).

5-(1-Bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (AI7)

The product was isolated as a colorless oil (320 mg, 60%): ¹H NMR (400MHz, CDCl₃) δ 7.45 (s, 2H), 5.00 (m, 2H); EIMS m/z 324.00 ([M]⁺).

4-(1-Bromo-2,2,2-trifluoroethyl)-1,2-dichlorobenzene (AI8)

The product was isolated as a colorless oil (300 mg, 60%): ¹H NMR (400MHz, CDCl₃) δ 7.63 (s, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m, 1H);EIMS m/z 306.00 ([M]⁺).

Example 2 Preparation of N-methyl-4-vinylbenzamide (AI9)

Step 1. 4-Vinylbenzoyl chloride (AI10)

To a stirred solution of 4-vinylbenzoic acid (1 g, 6.75 mmol) in CH₂Cl₂(20 mL) at 0° C. were added a catalytic amount of N,N-dimethylformamide(DMF) and oxalyl chloride (1.27 g, 10.12 mmol) dropwise over a period of15 minutes (min) The reaction mixture was stirred at 25° C. for 6 h.After the reaction was deemed complete by TLC, the reaction mixture wasconcentrated under reduced pressure to give the crude acid chloride.

Step 2. N-Methyl-4-vinylbenzamide (AI9)

To 1 M N-methylamine in THF (13.5 mL, 13.5 mmol) at 0° C. were addedtriethylamine (Et₃N; 1.34 mL, 10.12 mmol) and the acid chloride fromStep 1 above in THF (10 mL), and the reaction mixture was stirred at 25°C. for 3 h. After the reaction was deemed complete by TLC, the reactionmixture was quenched with water and then was extracted with EtOAc (3×).The combined EtOAc layer was washed with brine and dried over Na₂SO₄ andconcentrated under reduced pressure to afford the title compound as anoff-white solid (650 mg, 60%): ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=8.0Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.79 (m, 1H), 6.20 (br s, 1H), 5.82 (d,J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H); ESIMS m/z 161.95 ([M+H]⁺).

The following compounds were made in accordance with the proceduresdisclosed in accordance with Example 2.

N,N-dimethyl-4-vinylbenzamide (AI11)

The product was isolated as an off-white solid (650 mg, 60%): ¹H NMR(400 MHz, CDCl₃) δ 7.42 (m, 4H), 6.71 (m, 1H), 5.80 (d, J=17.6 Hz, 1H),5.31 (d, J=10.8 Hz, 1H), 3.05 (s, 3H), 3.00 (s, 3H); ESIMS m/z 176.01([M+H]⁺).

N-(2,2,3-trifluoromethyl)-4-vinylbenzamide (AI12)

The product was isolated as an off-white solid (900 mg, 60%): ¹H NMR(400 MHz, CDCl₃) δ 7.76 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.79(m, 1H), 6.20 (br s, 1H), 5.82 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz,1H), 4.19 (m, 2H); ESIMS m/z 230.06 ([M+H]⁺).

Morpholino(4-vinylphenyl)methanone (AI13)

The product was isolated as a white solid (850 mg, 60%): ESIMS m/z218.12 ([M+H]⁺).

Example 3 Preparation of ethyl 2-methyl-4-vinylbenzoate (AI14)

Step 1. 4-Formyl-2-methylbenzoic acid (AI15)

To a stirred solution of 4-bromo-2-methylbenzoic acid (10 g, 46.4 mmol)in dry THF (360 mL) at −78° C. was added n-butyllithium (n-BuLi, 1.6 Msolution in hexane; 58.17 mL, 93.0 mmol) and DMF (8 mL). The reactionmixture was stirred at −78° C. for 1 h then was warmed to 25° C. andstirred for 1 h. The reaction mixture was quenched with 1 N HCl solutionand extracted with EtOAc. The combined EtOAc extracts were washed withbrine and dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was washed with n-hexane to afford the title compound as a solid(3.0 g, 40%): mp 196-198° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 13.32 (br s,1H), 10.05 (s, 1H), 7.98 (m, 1H), 7.84 (m, 2H), 2.61 (s, 3H); ESIMS m/z163.00 ([M−H]⁻).

Step 2. Ethyl 4-formyl-2-methylbenzoate (AI16)

To a stirred solution of 4-formyl-2-methylbenzoic acid (3 g, 18.2 mmol)in ethyl alcohol (EtOH; 30 mL) was added sulfuric acid (H₂SO₄, x M; 2mL), and the reaction mixture was heated at 80° C. for 18 h. Thereaction mixture was cooled to 25° C. and concentrated under reducedpressure. The residue was diluted with EtOAc and washed with H₂O. Thecombined EtOAc extracts were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to afford the title compound as asolid (2.8 g, 80%): ¹H NMR (400 MHz, CDCl₃) δ 10.05 (s, 1H), 8.04 (m,1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).

Step 3. ethyl 2-methyl-4-vinylbenzoate (AI14)

To a stirred solution of ethyl 4-formyl-2-methylbenzoate (2.8 g, 4 mmol)in 1,4-dioxane (20 mL) were added potassium carbonate (K₂CO₃; 3.01 g,21.87 mmol) and methyltriphenyl phosphonium bromide (7.8 g, 21.87 mmol)at 25° C. Then the reaction mixture was heated at 100° C. for 18 h.After the reaction was deemed complete by TLC, the reaction mixture wascooled to 25° C. and filtered, and the filtrate was concentrated underreduced pressure. The crude compound was purified by flashchromatography (SiO₂, 100-200 mesh; eluting with 25-30% EtOAc inn-Hexane) to afford the title compound as a solid (2.0 g, 72%): ¹H NMR(400 MHz, CDCl₃) δ 7.86 (m, 1H), 7.27 (m, 2H), 6.68 (dd, J=17.6, 10.8Hz, 1H), 5.84 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H), 4.39 (m, 2H),2.60 (s, 3H), 1.40 (m, 3H); ESIMS m/z 191.10 ([M−H]⁻); IR (thin film)2980, 1716, 1257 cm⁻¹.

Example 4 Preparation of tert-butyl 2-chloro-4-vinylbenzoate (AI17)

Step 1. tert-Butyl 4-bromo-2-chlorobenzoate (AI18)

To a stirred solution of 4-bromo-2-chlorobenzoic acid (5 g, 21.37 mmol)in THF (30 mL) was added di-tert-butyl dicarbonate (25.5 g, 25.58 mmol),Et₃N (3.2 g, 31.98 mmol) and 4-(dimethylamino)pyridine (DMAP; 0.78 g,6.398 mmol), and the reaction mixture was stirred at 25° C. for 18 h.The reaction mixture was diluted with EtOAc and washed with H₂O. Thecombined organic layer was washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by flashchromatography (SiO₂, 100-200 mesh; eluting with 2-3% EtOAc in n-hexane)to afford the title compound as a liquid (3.2 g, 51%): ¹H NMR (400 MHz,CDCl₃) δ 7.62 (m, 2H), 7.44 (d, J=8.4 Hz, 1H), 1.59 (s, 9H); ESIMS m/z290.10 ([M+H]⁺); IR(thin film) 1728 cm⁻¹.

The following compounds were made in accordance with the proceduresdisclosed in Step 1 of Example 4.

tert-Butyl 2-bromo-4-iodobenzoate (AI19)

The product was isolated as a colorless oil (1.2 g, 50%): ¹H NMR (400MHz, CDCl₃) δ 8.01 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.0 Hz,1H), 1.59 (s, 9H); ESIMS m/z 382.10 ([M+H]⁺); IR(thin film) 1727 cm⁻¹.

tert-Butyl 4-bromo-2-(trifluoromethyl)benzoate (AI20)

The product was isolated as a colorless oil (1 g, 52%): ¹H NMR (400 MHz,CDCl₃) δ 7.85 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H),1.57 (s, 9H); ESIMS m/z 324.10 ([M+H]⁺); IR (thin film) 1725 cm⁻¹.

Step 2. tert-butyl 2-chloro-4-vinylbenzoate (AI17)

To a stirred solution of tert-butyl 4-bromo-2-chlorobenzoate (1.6 g,5.50 mmol) in toluene (20 mL) was addedtetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄; (0.31 mg, 0.27mmol), K₂CO₃ (2.27 g, 16.5 mmol) and vinylboronic anhydride pyridinecomplex (2.0 g, 8.3 mmol) and the reaction mixture was heated to refluxfor 16 h. The reaction mixture was filtered, and the filtrate was washedwith H₂O and brine, dried over Na₂SO₄ and concentrated under reducedpressure. Purification by flash column chromatography (SiO₂, 100-200mesh; eluting with 5-6% EtOAc in n-hexane) afforded the title compoundas a liquid (0.6 g, 46%): ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J=8.1 Hz,1H), 7.44 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.69 (dd, J=17.6, 10.8 Hz,1H), 5.85 (d, J=17.6 Hz, 1H), 5.40 (d, J=10.8 Hz, 1H), 1.60 (s, 9H);ESIMS m/z 238.95 ([M+H]⁺); IR (thin film) 2931, 1725, 1134 cm⁻¹.

The following compounds were made in accordance with the proceduresdisclosed in Step 2 of Example 4.

tert-Butyl 2-bromo-4-vinylbenzoate (AI21)

The product was isolated as a colorless oil (1 g, 52%): ¹H NMR (400 MHz,CDCl₃) δ 7.68 (m, 2H), 7.36 (d, J=8.0 Hz, 1H), 6.68 (dd, J=17.6, 10.8Hz, 1H), 5.84 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H), 1.60 (s, 9H);ESIMS m/z 282.10 ([M+H]⁺); IR (thin film) 2978, 1724, 1130 cm⁻¹.

tert-Butyl 2-(trifluoromethyl)-4-vinylbenzoate (AI22)

The product was isolated as a colorless oil (1.2 g, 50%): ¹H NMR (400MHz, CDCl₃) δ 7.71 (d, J=6.4 Hz, 2H), 7.59 (d, J=7.6 Hz, 1H), 6.77 (dd,J=17.6, 10.8 Hz, 1H), 5.89 (d, J=17.6 Hz, 1H), 5.44 (d, J=10.8 Hz, 1H),1.58 (s, 9H); ESIMS m/z 272.20 ([M+H]⁺); IR (thin film) 2982, 1727, 1159cm⁻¹.

Example 5 Preparation of tert-butyl 2-cyano-4-vinylbenzoate (AI23)

To a stirred solution of tert-butyl 2-bromo-4-vinylbenzoate (0.5 g, 1.77mmol) in DMF (20 mL) was added copper(I) cyanide (CuCN; 0.23 g, 2.65mmol), and the reaction mixture was heated at 140° C. for 3 h. Thereaction mixture was cooled to 25° C., diluted with H₂O, and extractedwith EtOAc. The combined organic layer was washed with brine, dried overNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by flash chromatography (SiO₂, 100-200 mesh; eluting with 15%EtOAc in n-hexane) to afford the title compound as a white solid (0.3 g,72%): mp 51-53° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H), 7.77 (s,1H), 7.64 (d, J=8.4 Hz, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.93 (d,J=17.6 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 229.84([M+H]⁺); IR (thin film) 2370, 1709, 1142 cm⁻¹.

Example 6 Preparation of ethyl 2-bromo-4-iodobenzoate (AI46)

To a stirred solution of 4-iodo-2-bromobenzoic acid (5 g, 15.29 mmol) inethyl alcohol (EtOH; 100 mL) was added sulfuric acid (H₂SO₄; 5 mL), andthe reaction mixture was heated at 80° C. for 18 h. The reaction mixturewas cooled to 25° C. and concentrated under reduced pressure. Theresidue was diluted with EtOAc (2×100 mL) and washed with H₂O (100 mL).The combined EtOAc extracts were washed with brine, dried over Na₂SO₄and concentrated under reduced pressure to afford the compound as a paleyellow solid (5 g, 92%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (d, J=1.2 Hz,1H), 7.71 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.41 (q, J=7.2 Hz,2H), 1.41 (t, J=7.2 Hz, 3H).

The following compounds were made in accordance with the proceduresdisclosed in Example 6.

Ethyl 4-bromo-2-chlorobenzoate (AI47)

The title compound was isolated as an off-white solid (2.0 g, 80%): ¹HNMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=1.2 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H),7.65 (d, J=8.4 Hz, 1H), 4.65 (q, J=7.2 Hz, 2H), 1.56 (t, J=7.2 Hz, 3H).

Ethyl 4-bromo-2-methylbenzoate (AI48)

The title compound was isolated as a pale yellow liquid (3.0 g, 83%): ¹HNMR (400 MHz, CDCl₃) δ 7.79 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.39 (d,J=8.4 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.40 (t, J=7.2 Hz,3H) ESIMS m/z 229.11 ([M+H]⁺); IR (thin film) 1725 cm⁻¹.

Ethyl 4-bromo-2-fluorobenzoate (AI49)

The title compound was isolated as a colorless liquid (9.0 g, 79%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.84 (t, J=8.4 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H),7.58 (d, J=1.6 Hz, 1H), 4.34 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H);ESIMS m/z 246.99 ([M+H]⁺), IR (thin film) 1734 cm⁻¹.

Example 7 Preparation of ethyl 4-bromo-2-ethylbenzoate (AI50)

To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.17 mmol)in THF (16 mL), was added 1.0 M ethyl magnesium bromide in THF (32 mL,32.0 mmol) dropwise at 0° C. and the resultant reaction mixture wasstirred at RT for 18 h. The reaction mixture was quenched with 2 N HCland extracted with ethyl acetate. The combined ethyl acetate layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford crude 4-bromo-2-ethylbenzoic acid as a colorless liquid that wasused in the next step without purification (0.4 g): ¹H NMR (400 MHz,CDCl₃) δ 7.64 (d, J=8.4 Hz, 1H), 7.47 (m, 1H), 7.43 (m, 1H), 2.95 (q,J=4.0 Hz, 2H), 1.32 (t, J=4.0 Hz, 3H); ESIMS m/z 228.97 ([M+H]⁺).

The title compound was synthesized from 4-bromo-2-ethylbenzoic acid inaccordance to the procedure in Example 6, isolated as a colorless liquid(0.15 g, 68%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (d, J=8.4 Hz, 1H), 7.47(m, 2H), 4.40 (q, J=7.2 Hz, 2H), 3.06 (q, J=7.6 Hz, 2H), 1.42 (t, J=7.2Hz, 3H), 1.26 (t, J=7.6 Hz, 3H); ESIMS m/z 226.96 ([M−H]⁻); IR (thinfilm) 3443, 1686, 568 cm⁻¹.

Example 8 Preparation of ethyl 2-bromo-4-vinylbenzoate (AI51)

To a stirred solution of ethyl 2-bromo-4-iodobenzoate (5 g, 14.3 mmol)in THF/water (100 mL, 9:1) was added potassium vinyltrifluoroborate(1.89 g, 14.3 mmol), Cs₂CO₃ (18.27 g, 56.07 mmol) and triphenylphosphine(0.22 g, 0.85 mmol) and the reaction mixture was degassed with argon for20 min, then charged with PdCl₂ (0.05 g, 0.28 mmol). The reactionmixture was heated to reflux for 16 h. The reaction mixture was cooledto RT and filtered through a celite bed and washed with ethyl acetate.The filtrate was again extracted with ethyl acetate and the combinedorganic layers washed with water and brine, dried over Na₂SO₄ andconcentrated under reduced pressure to afford crude compound. The crudecompound was purified by column chromatography (SiO₂, 100-200 mesh;eluting with 2% ethyl acetate/petroleum ether) to afford the titlecompound as a light brown gummy material (2 g, 56%): ¹H NMR (400 MHz,CDCl₃) δ 7.78 (d, J=8.4 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 6.69 (dd, J=17.6, 10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.42(d, J=11.2 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=3.6 Hz, 3H);ESIMS m/z 255.18 ([M+H]⁺); IR (thin film) 1729 cm⁻¹.

The following compounds were made in accordance with the proceduresdisclosed in Example 8.

Ethyl 2-methyl-4-vinylbenzoate (AI52)

The title compound was isolated as a colorless liquid (0.8 g, 80%): ¹HNMR (400 MHz, CDCl₃) δ 7.89 (d, J=8.4 Hz, 1H), 7.27 (m, 2H), 6.79 (dd,J=17.6, 10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.42 (d, J=11.2 Hz, 1H),4.42 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.43 (t, J=7.2 Hz, 3H); ESIMS m/z191.10 ([M+H]⁺); IR (thin film) 1717, 1257 cm⁻¹.

Ethyl 2-fluoro-4-vinylbenzoate (AI53)

The title compound was isolated as a pale yellow liquid (2.0 g, 50%): ¹HNMR (400 MHz, DMSO-d₆) δ 7.87 (t, J=8.0 Hz, 1H), 7.51 (d, J=16.0 Hz,1H), 7.48 (d, J=16.0 Hz, 1H), 6.82 (dd, J=17.6, 10.8 Hz, 1H), 6.09 (d,J=17.6 Hz, 1H), 5.50 (d, J=10.8 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.35(t, J=7.2 Hz, 3H); ESIMS m/z 195.19 ([M+H]⁺); IR (thin film) 1728 cm⁻¹.

Example 9 Preparation of ethyl 2-chloro-4-vinylbenzoate (AI54)

To a stirred solution of ethyl 2-chloro-4-bromobenzoate (2 g, 7.63 mmol)in dimethylsulfoxide (20 mL) was added potassium vinyltrifluoroborate(3.06 g, 22.9 mmol) and potassium carbonate (3.16 g, 22.9 mmol). Thereaction mixture was degassed with argon for 30 minBistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride(0.27 g, 0.38 mmol) was added and the reaction mixture was heated to 80°C. for 1 h. The reaction mixture was diluted with water (100 mL),extracted with ethyl acetate (2×50 mL), washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to obtain the compound asbrown gummy material (1.1 g, 69%): ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d,J=8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.70 (dd, J=17.6,11.2 Hz, 1H), 5.87 (d, J=17.6 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H), 4.41 (q,J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H); ESIMS m/z 211.22 ([M+H]⁺); IR(thin film) 1729, 886 cm⁻¹.

The following compounds were made in accordance with the proceduresdisclosed in Example 9.

Ethyl 2-ethyl-4-vinylbenzoate (AI55)

The title compound was isolated as a color less liquid (1.0 g, 66%): ¹HNMR (300 MHz, CDCl₃) δ 7.85 (m, 1H), 7.29 (m, 2H), 6.76 (d, J=10.8 Hz,1H), 5.86 (d, J=17.6 Hz, 1H), 5.36 (d, J=10.5 Hz, 1H), 4.41 (q, J=7.2Hz, 2H), 3.10 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H), 1.30 (t, J=7.2Hz, 3H); ESIMS m/z 205.26 ([M+H]⁺); IR (thin film) 1720, 1607, 1263cm⁻¹.

Methyl 2-methoxy-4-vinylbenzoate (AI56)

The title compound was isolated as a pale yellow liquid (1.2 g, 75%): ¹HNMR (400 MHz, CDCl₃) δ 7.79 (d, J=8.0 Hz, 1H), 7.04 (d, J=1.2 Hz, 1H),6.97 (s, 1H), 6.74 (dd, J=11.2, 11.2 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H),5.39 (d, J=17.6 Hz, 1H) 3.93 (s, 3H), 3.91 (s, 3H). ESIMS m/z 193.18([M+H]⁺); IR (thin film) 1732 cm⁻¹,

Example 10 Preparation of (E)-ethyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate(AI24)

To a stirred solution of ethyl 2-methyl-4-vinylbenzoate (2.0 g, 10.5mmol) in 1,2-dichlorobenzene (25 mL) were added1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (6.44 g, 21.0mmol), copper(I) chloride (CuCl; 208 mg, 21 mmol) and 2,2bipyridyl (0.65g, 4.1 mmol). The reaction mixture was degassed with argon for 30 minand then stirred at 180° C. for 24 h. After the reaction was deemedcomplete by TLC, the reaction mixture was cooled to 25° C. and filtered,and the filtrate was concentrated under reduced pressure. Purificationby flash chromatography (SiO₂, 100-200 mesh; eluting with 25-30% EtOAcin petroleum ether) afforded the title compound as a solid (1.7 g, 40%):¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J=8.0 Hz, 1H), 7.37 (m, 1H),7.27-7.24 (m, 4H), 6.59 (d, J=16.0 Hz, 1H), 6.59 (dd, J=16.0, 8.0 Hz,1H), 4.38 (q, J=7.2 Hz, 2H), 4.08 (m, 1H), 2.62 (s, 3H), 1.42 (t, J=7.2Hz, 3H); ESIMS m/z 415.06 ([M−H]⁻); IR (thin film) 1717, 1255, 1114cm⁻¹.

Compounds AI25, AI57-AI68 and AC1-AC5 (Table 1) were made in accordancewith the procedures disclosed in Example 10.

(E)-Ethyl4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)-benzoicacid (AI25)

The product was isolated as a pale brown gummy liquid (500 mg, 40%): ¹HNMR (400 MHz, CDCl₃) δ 7.79 (d, J=8.0 Hz, 1H), 7.71 (m, 1H), 7.61 (d,J=7.6 Hz, 1H), 7.42 (s, 2H), 6.70 (d, J=16.0 Hz, 1H), 6.57 (dd, J=16.0,8.0 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.19 (m, 1H), 1.40 (t, J=7.6 Hz,3H); ESIMS m/z 502.99 ([M−H]⁻); IR (thin film) 1730, 1201, 1120, 749cm⁻¹.

(E)-Ethyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluorobenzoate(AI57)

¹H NMR (400 MHz, CDCl₃) δ 7.38 (s, 1H), 7.26 (s, 3H), 7.21 (d, J=8.4 Hz,1H), 7.16 (d, J=11.6 Hz, 1H), 6.59 (d, J=16.0 Hz, 1H), 6.47 (dd, J=16.0,8.0 Hz, 1H), 4.41 (q, J=6.8 Hz, 2H), 4.18 (m, 1H), 1.41 (t, J=6.8 Hz,3H); ESIMS m/z 419.33 ([M−H]⁻); IR (thin film) 1723, 1115, 802 cm⁻¹.

(E)-Ethyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-bromobenzoate(AI58)

¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.38 (m,2H), 7.26 (m, 2H), 6.56 (d, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 7.6 Hz,1H), 4.42 (q, J=7.2 Hz, 2H), 4.39 (m, 1H), 1.42 (t, J=7.2 Hz, 3H); ESIMSm/z 481.22 ([M−H]⁻); IR (thin film) 1727, 1114, 801, 685 cm⁻¹.

(E)-Ethyl 2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoate (AI59)

¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J=8.0 Hz, 1H), 7.67 (d, J=1.6 Hz,1H), 7.40 (s, 2H), 7.36 (d, J=1.6 Hz, 1H), 6.56 (d, J=16.0 Hz, 1H), 6.44(dd, J=16.0, 7.6 Hz, 1H), 4.42 (q, J=6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t,J=6.8 Hz, 3H); ESIMS m/z 514.74 ([m−H]⁻); IR (thin film) 1726, 1115,808, 620 cm⁻¹.

(E)-Ethyl 2-methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoate (AI60)

The title compound was isolated as a light brown gummy material: ¹H NMR(400 MHz, CDCl₃) δ 7.90 (d, J=8.8 Hz, 1H), 7.34 (d, J=6.0 Hz, 2H), 7.25(d, J=7.2 Hz, 2H), 6.59 (d, J=16.0 Hz, 1H), 6.42 (dd, J=16.0, 8.0 Hz,1H), 4.38 (q, J=7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, J=7.2Hz, 3H).

(E)-Ethyl2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoate(AI61)

¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J=8.0 Hz, 1H), 7.46 (d, J=1.6 Hz,1H), 7.40 (s, 2H), 7.31 (d, J=1.6 Hz, 1H), 6.57 (d, J=16.0 Hz, 1H), 6.44(dd, J=16.0 Hz, 8.0 Hz, 1H), 4.42 (q, J=6.8 Hz, 2H), 4.15 (m, 1H), 1.42(t, J=6.8 Hz, 3H); ESIMS m/z 470.73 ([M−H]⁻); IR (thin film) 1726, 1115,809, 3072 cm⁻¹.

(E)-Ethyl4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzoate(AI62)

The title compound was isolated as a pale brown liquid (1.0 g, 46.3%):¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.61 (d,J=7.6 Hz, 1H), 7.41 (s, 2H) 6.65 (d, J=16.0 Hz, 1H), 6.49 (dd, J=16.0,8.0 Hz, 1H), 4.42 (q, J=7.6 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J=7.6 Hz,3H); ESIMS m/z 502.99 ([M−H]⁻); IR (thin film) 1730, 1202, 1120, 750cm⁻¹.

(E)-Ethyl2-chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate(AI63)

¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J=6.0 Hz, 1H), 7.46 (d, J=1.8 Hz,2H), 7.34 (m, 1H), 7.24 (m, 1H), 6.57 (d, J=16.2 Hz, 1H), 6.45 (dd,J=16.2, 7.2 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 4.13 (m, 1H), 1.41 (t,J=7.2 Hz, 3H); ESIMS m/z 455.0 ([M+H]⁺); IR (thin film) 1728, 1115, 817cm⁻¹.

(E)-Ethyl2-fluoro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate(AI64)

¹H NMR (400 MHz, CDCl₃) δ 7.93 (t, J=7.6 Hz, 1H), 7.34 (d, J=5.6 Hz,2H), 7.21 (d, J=8.0 Hz, 1H), 7.16 (d, J=11.6 Hz, 1H), 6.59 (d, J=16.0Hz, 1H), 6.49 (dd, J=16.0, 7.6 Hz, 1H), 4.42 (q, J=7.6 Hz, 2H), 4.13 (m,1H), 1.41 (t, J=7.6 Hz, 3H); ESIMS m/z 436.81 ([M−H]⁻); IR (thin film)1725 cm⁻¹.

(E)-Ethyl2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate(AI65)

¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.36 (m,3H), 6.56 (d, J=15.6 Hz, 1H), 6.44 (dd, J=15.6, 8.0 Hz, 1H), 4.42 (q,J=6.8 Hz, 2H), 4.10 (m, 1H), 1.42 (t, J=6.8 Hz, 3H); ESIMS m/z 498.74([M−H]⁻); IR (thin film) 1726, 1114, 820, 623 cm⁻¹.

(E)-Ethyl2-methyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate(AI66)

The title compound was isolated as a brown semi-solid: ¹H NMR (400 MHz,CDCl₃) δ 7.90 (d, J=8.8 Hz, 1H), 7.34 (d, J=6.0 Hz, 2H), 7.25 (d, J=7.2Hz, 2H), 6.59 (d, J=16.0 Hz, 1H), 6.42 (dd, J=16.0 Hz, 8.0 Hz, 1H), 4.38(q, J=7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, J=7.2 Hz, 3H);ESIMS m/z 432.90 ([m−H]⁻); IR (thin film) 1715 cm⁻¹.

(E)-Methyl2-methoxy-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate(AI67)

¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=8.4 Hz, 1H), 7.35 (d, J=6.0 Hz,2H), 7.03 (d, J=1.2 Hz, 1H), 6.92 (s, 1H), 6.59 (d, J=15.6 Hz, 1H), 6.42(dd, J=15.6, 8.0 Hz, 1H), 4.13 (m, 1H), 3.93 (s, 3H), 3.88 (s, 3H);ESIMS m/z 437.29 ([M+H]⁺); IR (thin film) 1724 cm⁻¹.

(E)-Ethyl2-ethyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate(AI68)

¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J=8.0 Hz, 1H), 7.35 (d, J=9.6 Hz,2H), 7.26 (m, 1H), 7.24 (m, 1H), 6.60 (d, J=15.6 Hz, 1H), 6.42 (dd,J=15.6, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.14 (m, 1H), 3.01 (q,J=7.6 Hz 2H), 1.41 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H); ESIMS m/z447.05 ([M−H]⁻); IR (thin film) 1715, 1115, 817 cm⁻¹.

Example 11 Preparation of(E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoicacid (AI32)

To a stirred solution of (E)-ethyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate(1.7 g, 4.0 mmol) in 1,4-dioxane (10 mL) was added 11 N HCl (30 mL), andthe reaction mixture was heated at 100° C. for 48 h. The reactionmixture was cooled to 25° C. and concentrated under reduced pressure.The residue was diluted with H₂O and extracted with chloroform (CHCl₃).The combined organic layer was dried over Na₂SO₄ and concentrated underreduced pressure, and the crude compound was washed with n-hexane toafford the title compound as a white solid (0.7 g, 50%): mp 142-143° C.;¹H NMR (400 MHz, DMSO-d₆) δ 12.62 (br s, 1H), 7.81 (d, J=8.0 Hz, 1H),7.66 (s, 3H), 7.52-7.44 (m, 2H), 6.89 (dd, J=16.0, 8.0 Hz, 1H),6.78-6.74 (d, J=16.0 Hz, 1H), 4.84 (m, 1H), 2.50 (s, 3H); ESIMS m/z387.05 ([M−H]⁻); IR (thin film) 3448, 1701, 1109, 777 cm⁻¹.

The following compounds were made in accordance with the proceduresdisclosed in Example 11.

(E)-2-Methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoicacid (AI26)

The product was isolated as a pale brown gummy liquid (1 g, 46%): ¹H NMR(400 MHz, CDCl₃) δ 7.97 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H),7.41 (s, 2H), 6.68 (d, J=16.0 Hz, 1H), 6.53 (dd, J=16.0, 8.0 Hz, 1H),4.16 (m, 1H), 2.50 (s, 3H); ESIMS m/z 422.67 ([M−H]⁻).

(E)-2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoicacid (AI27)

The product was isolated as an off-white semi-solid (1 g, 45%): ¹H NMR(400 MHz, CDCl₃) δ 7.99 (d, J=8.4 Hz, 1H), 7.50 (m, 1H), 7.40 (s, 1H),7.36 (m, 2H), 6.59 (d, J=15.6 Hz, 1H), 6.48 (dd, J=15.6, 7.6 Hz, 1H),4.14 (m, 1H); ESIMS m/z 442.72 ([M−H]⁻); IR (thin film) 3472, 1704,1113, 808 cm⁻¹.

(E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoicacid (AI28)

The product was isolated as a brown solid (1 g, 45%): mp 70-71° C.; ¹HNMR (400 MHz, CDCl₃) δ 7.99 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.40 (m,3H), 6.58 (d, J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 4.14 (m,1H); ESIMS m/z 484.75 ([M−H]⁻); IR (thin film) 3468, 1700 cm⁻¹.

(E)-2-Cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoicacid (AI29)

The product was isolated as an off-white solid (500 mg, 45%): mp100-101° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 7.85 (d, J=7.6 Hz,1H), 7.72 (d, J=8.0 Hz, 1H), 7.65 (br s, 1H), 7.42 (s, 2H), 6.73 (d,J=16.0 Hz, 1H), 6.58 (dd, J=16.0, 8.0 Hz, 1H), 4.19 (m, 1H); ESIMS m/z431.93 ([M−H]⁻).

E)-4-(3-(3,4-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoicacid (AI30)

The product was isolated as a pale brown liquid (500 mg, 46%): ¹H NMR(400 MHz, CDCl₃) δ 8.03 (m, 1H), 7.49 (m, 2H), 7.29 (m, 1H), 7.22 (m,2H), 6.73 (d, J=16.0 Hz, 1H), 6.58 (dd, J=16.0, 7.8 Hz, 1H), 4.16 (m,1H), 2.64 (s, 3H); ESIMS m/z 386.84 ([M−H]⁻); IR (thin film) 3428, 1690,1113, 780 cm⁻¹.

(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoicacid (AI31)

The product was isolated as a white solid (500 mg, 50%): mp 91-93° C.;¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, J=8.0 Hz, 1H), 7.35 (d, J=5.6 Hz,1H), 7.30 (m, 3H), 6.61 (d, J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz,1H), 4.13 (m, 1H), 2.65 (s, 3H); ESIMS m/z 406.87 ([M−H]⁻).

(E)-4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzoicacid (AI33)

The product was isolated as a white solid (500 mg, 45%): mp 142-143° C.;¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m,1H), 7.41 (s, 2H), 6.68 (d, J=16.0 Hz, 1H), 6.53 (dd, J=16.0, 8.0 Hz,1H), 4.16 (m, 1H); ESIMS m/z 474.87 ([M−H]⁻).

(E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoicacid (AI69)

The title compound was isolated as a brown solid (0.8 g, 28%): ¹H NMR(400 MHz, CDCl₃) δ 13.42 (br, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.94 (m, 2H),7.75 (d, J=8.1 Hz, 1H), 7.65 (m, 1H), 7.06 (dd, J=15.9, 9.0 Hz, 1H),6.80 (d, J=15.9 Hz, 1H), 4.91 (m, 1H); ESIMS m/z 484.75 ([M−H]⁻); IR(thin film) 3469, 1700 cm⁻¹.

(E)-2-Bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoicacid (AI70)

The title compound was isolated as a yellow liquid (0.3 g, crude): ¹HNMR (300 MHz, CDCl₃) δ 7.79 (d, J=8.1 Hz, 1H), 7.67 (s, 1H), 7.34 (m,3H), 6.56 (d, J=15.9 Hz, 1H), 6.45 (dd, J=15.9, 7.6 Hz, 1H), 4.43 (m,1H); ESIMS m/z 471.0 ([M−H]⁻).

(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-ethylbenzoicacid (AI71)

The title compound was isolated as a brown gummy material (0.2 g,crude): ¹H NMR (300 MHz, DMSO-d₆) δ 12.5 (br, 1H), 7.85 (d, J=6.3 Hz,2H), 7.75 (d, J=8.1 Hz, 1H), 7.52 (m, 2H), 6.96 (dd, J=8.7, 8.7 Hz, 1H),6.78 (d, J=15.6 Hz, 1H), 4.80 (m, 1H), 4.06 (q, J=7.2 Hz, 2H), 1.33 (t,J=7.2 Hz, 3H); ESIMS m/z 419.06 ([M−H]⁻).

(E)-2-Chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoicacid (AI72)

The title compound was isolated as a yellow liquid (0.7 g, 95%): ¹H NMR(300 MHz, CDCl₃) δ 7.85 (d, J=6.0 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.41(s, 3H), 6.57 (d, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 8.0 Hz, 1H), 4.16(m, 1H); ESIMS m/z 455.0 ([M+H]⁺); IR (thin film) 1728, 1115, 817 cm⁻¹.

(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoicacid (AI73)

The title compound was isolated as a light brown gummy material (0.7 g,38%): mp 91-93° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, J=8.0 Hz, 1H),7.35 (d, J=5.6 Hz, 1H), 7.30 (m, 3H), 6.10 (d, J=16.0 Hz, 1H), 6.46 (dd,J=16.0, 8.0 Hz, 1H), 4.03 (m, 1H), 2.65 (s, 3H); ESIMS m/z 406.87([M−H]⁻).

(E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluorobenzoicacid (AI74)

The title compound was isolated as a light brown liquid (0.3 g, crude):ESIMS m/z 393.15 ([M−H]⁻).

(E)-2-Bromo-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)benzoicacid (AI75)

The title compound was isolated as a light brown liquid (0.35 g, crude):ESIMS m/z 451.91 ([M−H]⁻).

Prophetically, compounds AI34, AI36-AI41, AI44-AI45 (Table 1) could bemade in accordance with the procedures disclosed in Example 10, orExamples 10 and 11.

Example 12 Preparation of(E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methyl-N-(2,2,2-trifluoroethyl)benzamide(AC6)

To a stirred solution of(E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoicacid in DMF was added 2,2,2-trifluoroethylamine, 1-hydroxybenzotriazolehydrate (HOBt.H₂O), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (EDC.HCl) and N,N-diisopropylethylamine (DIEA), and thereaction mixture was stirred at 25° C. for 18 h. The reaction mixturewas diluted with H₂O and extracted with EtOAc. The combined organiclayer was washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure. Purification by flash column chromatography (SiO₂,100-200 mesh; eluting with hexane:EtOAc afforded a white semi-solid (110mg, 50%): ¹H NMR (400 MHz, CDCl₃) 7.40 (m, 2H), 7.26 (m, 3H), 6.56 (d,J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 5.82 (br s, 1H), 4.08 (m,3H), 2.52 (s, 3H); ESIMS m/z 468.40 ([M−H]⁻); IR (thin film) 1657, 1113,804 cm⁻¹.

Compounds AC7-AC38, AC40-AC58, AC110-AC112, AC117, and AC118 (Table 1)were made in accordance with the procedures disclosed in Example 12.

Example 13 Preparation of4-((E)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methyl-N-((pyrimidin-5-yl)methyl)benzamide(AC39)

To a stirred solution of (pyrimidin-5-yl)methanamine (0.15 g, 1.43 mmol)in CH₂Cl₂ (10 mL) was added drop wise trimethylaluminum (2 M solution intoluene; 0.71 mL, 1.43 mmol), and the reaction mixture was stirred at25° C. for 30 min A solution of ethyl4-((E)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate(0.3 g, 0.71 mmol) in CH₂Cl₂ was added drop wise to the reaction mixtureat 25° C. The reaction mixture was stirred at reflux for 18 h, cooled to25° C., quenched with 0.5 N HCl solution (50 mL) and extracted withEtOAc (2×50 mL). The combined organic extracts were washed with brine,dried over Na₂SO₄, and concentrated under reduced pressure. The crudecompound was purified by flash chromatography (SiO₂, 100-200 mesh;eluting with 40% EtOAc in n-hexane) to afford the title compound (0.18g, 55%): mp 141-144° C.; ¹H (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.79 (s,2H), 7.37 (m, 2H), 7.23 (m, 2H), 7.21 (m, 1H), 6.57 (d, J=16.0 Hz, 1H),6.40 (dd, J=16.0, 7.6 Hz 1H), 6.21 (m, 1H), 4.65 (s, 2H), 4.11 (m, 1H),2.46 (s, 3H); ESIMS m/z 477.83 ([M−H]⁻).

Example 14 Preparation of(E)-2-chloro-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide(AC64)

To a stirred solution of glycine amide (0.15 g, 0.58 mmol) in CH₂Cl₂ (5mL) was added trimethylaluminum (2 M solution in toluene; 1.45 mL, 2.91mmol) dropwise, and the reaction mixture was stirred at 28° C. for 30min A solution of (E)-ethyl2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoate(0.3 g, 0.58 mmol) in CH₂Cl₂ (5 mL) was added drop wise to the reactionmixture at 28° C. The reaction mixture was stirred at reflux for 18 h,cooled to 25° C., quenched with 1N HCl solution (50 mL) and extractedwith CH₂Cl₂ (2×50 mL). The combined organic extracts were washed withbrine, dried over Na₂SO₄, and concentrated under reduced pressure. Thecrude compound was purified by flash chromatography (SiO₂, 100-200 mesh;eluting with 40% EtOAc in n-hexane) to afford the title compound asyellow solid (0.15 g, 50%): mp 83-85° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.72(d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 2H), 7.36 (d, J=6.8 Hz, 1H),7.05 (t, J=5.2 Hz, 1H), 6.70 (t, J=5.2 Hz, 1H), 6.57 (d, J=15.6 Hz, 1H),6.44 (dd, J=15.6, 8.0 Hz, 1H), 4.23 (d, J=5.6 Hz, 2H), 4.15 (m, 1H),4.01 (m, 2H); ESIMS m/z 580.72 ([M−H]⁻).

Compounds AC59-AC75 (Table 1) were made in accordance with theprocedures disclosed in Example 14.

Example 15 Preparation of(E)-2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide(AC79)

To a stirred solution of(E)-2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoicacid (300 mg, 0.638 mmol) in DCM (5.0 mL) was added2-amino-N-(2,2,2-trifluoroethyl)acetamide (172. mg, 0.638 mmol) followedby benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) (364.5 mg, 0.701 mmol) and DIPEA (0.32 mL, 1.914 mmol), and theresultant reaction mixture was stirred at RT for 18 h. The reactionmixture was diluted with water and extracted with DCM. The combined DCMlayer was washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure. Purification by flash column chromatography (SiO₂,100-200 mesh; eluting with 40% ethyl acetate/petroleum ether) affordedthe title compound as an off-white solid (121 mg, 31%): ¹H NMR (400 MHz,CDCl₃) δ 8.69 (t, J=6.0 Hz, 1H), 8.58 (t, J=6.0 Hz, 1H), 7.92 (s, 1H),7.87 (d, J=6.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H),7.0 (m, 1H), 6.76 (d, J=15.6 Hz, 1H), 4.83 (t, J=8.0 Hz, 1H), 3.98 (m,4H); ESIMS m/z 610.97 ([M+H]⁺); IR (thin film) 3303, 1658, 1166, 817cm⁻¹.

Compounds AC76-AC80, AC96-AC102, and AC113 (Table 1) were made inaccordance with the procedures disclosed in Example 15.

Example 16 Preparation of(E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(1,1-dioxidothietan-3-yl)-2-fluorobenzamide(AC83)

To a stirred solution of(E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluoro-N-(thietan-3-yl)benzamide(100 mg, 0.2159 mmol) in acetone/water (1:1, 5.0 mL) was added oxone(266 mg, 0.4319 mmol) and the resultant reaction mixture was stirred atRT for 4 h. The reaction mixture was diluted with water and extractedwith ethyl acetate. The combined ethyl acetate layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. Purificationby flash column chromatography (SiO₂, 100-200 mesh; eluting with 30%ethyl acetate/pet ether) afforded the title compound as a off whitesolid (70.0 mg, 66%): ¹H NMR (400 MHz, CDCl₃) δ 8.07 (t, J=8.4 Hz, 1H),7.39 (t, J=1.6 Hz, 1H), 7.31 (d, J=1.2 Hz, 1H), 7.26 (m, 2H), 7.23 (m,2H), 7.19 (d, J=1.6 Hz, 1H), 6.60 (d, J=16.8 Hz, 1H), 6.49 (dd, J=16.8,7.6 Hz, 1H), 4.90 (m, 1H), 4.64 (m, 2H), 4.14 (m, 2H); ESIMS m/z 493.83([M−H]⁻); IR (thin film) 1527, 1113, 801, 1167, 1321 cm⁻¹.

Compounds AC81-AC87 (Table 1) were made in accordance with theprocedures disclosed in Example 16.

Example 17 Preparation of(E)-N-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-methylbenzamide(AC89)

A solution of(E)-N-(2-(2-(cyclopropanecarbonyl)hydrazinyl)-2-oxoethyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide(200 mg, 0.379 mmol) in POCl₃ (2.0 mL) was stirred at RT for 10 min,then the resultant reaction mixture was heated to 50° C. for 1 h. Thereaction mixture was quenched with ice water at 0° C. and extracted withethyl acetate. The combined ethyl acetate layer was washed withsaturated NaHCO₃ solution and brine solution, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. Purification by flashcolumn chromatography (SiO₂, 100-200 mesh; eluting with 50% ethylacetate/pet ether) afforded the title compound as a light brown gummymaterial (70.0 mg, 36%): ¹H NMR (400 MHz, CDCl₃) δ 7.43 (m, 2H), 7.27(m, 2H), 7.23 (m, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.41 (dd, J=16.0, 7.6Hz, 1H), 4.79 (d, J=5.6 Hz, 2H), 4.14 (m, 1H), 2.48 (s, 3H), 2.18 (m,1H), 1.16 (m, 4H); ESIMS m/z 509.89 ([M+H]⁺); IR (thin film) 1666, 1166,1112, 800 cm⁻¹.

Example 18 Preparation of(E)-2-bromo-N-(2-thioxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzothioamide(AC90)

To a stirred solution of(E)-2-bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide(400 mg, 0.638 mmol) in 5 mL of THF at RT was added2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson's reagent) (336 mg, 0.830 mmol) in one portion. The resultingreaction mixture was stirred for 18 h. TLC showed the reaction was notcomplete, therefore additional Lawesson's reagent (168 mg, 0.415 mmol)was added and reaction stirred for 48 h. After the reaction was deemedcomplete by TLC, the reaction mixture was concentrated under reducedpressure. Purification by flash chromatography (SiO₂, 230-400 mesh;eluting with 20% EtOAc in hexanes) afforded the title compound as ayellow glassy oil (188 mg, 44.7%):

¹H NMR (400 MHz, CDCl₃) δ 8.34 (m, 1H), 8.27 (m, 1H), 7.60 (d, J=1.6 Hz,1H), 7.49 (d, J=8.0 Hz, 2H), 7.40 (s, 2H), 7.36 (dd, J=8.2, 1.7 Hz, 1H),6.53 (d, J=16.0 Hz, 1H), 6.38 (dd, J=15.9, 7.9 Hz, 1H), 4.89 (d, J=8.4,5.5 Hz, 2H), 4.48 (qd, J=9.0, 6.0 Hz, 2H), 4.11 (m, 1H); ESIMS m/z 656.9([M−H]⁻).

Example 19 Preparation of(E)-2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenylthioamido)-N-(2,2,2-trifluoroethyl)acetamide(AC91)

To a stirred solution of(E)-2-bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide(400 mg, 0.638 mmol) in 5 mL of THF at RT was added Lawesson's reagent(64.5 mg, 0.160 mmol) in one portion. The resulting reaction mixture wasstirred for 18 h, after which time, the reaction mixture wasconcentrated under reduced pressure. Purification by flashchromatography (SiO₂, 230-400 mesh; eluting with 20% EtOAc in hexanes)afforded the title compounds as a yellow oil (18.5 mg, 4.51%): ¹H NMR(400 MHz, CDCl₃) δ 8.18 (t, J=5.0 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.47(d, J=8.0 Hz, 1H), 7.40 (s, 2H), 7.34 (dd, J=8.1, 1.6 Hz, 1H), 6.52 (m,2H), 6.37 (dd, J=15.9, 7.9 Hz, 1H), 4.54 (d, J=4.9 Hz, 2H), 4.12 (m,1H), 3.99 (qd, J=8.9, 6.5 Hz, 2H); ESIMS m/z 640.9 ([M−H]⁻).

The following compound was made in accordance with the proceduresdisclosed in Example 19.

(E)-2-bromo-N-(2-thioxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide(AC92)

The product was isolated as a colorless oil (17.9 mg, 4.36%):

¹H NMR (400 MHz, CDCl₃) δ 9.16 (d, J=6.1 Hz, 1H), 7.65 (d, J=1.6 Hz,1H), 7.57 (d, J=8.0 Hz, 1H), 7.41 (m, 3H), 7.21 (t, J=5.6 Hz, 1H), 6.55(d, J=15.9 Hz, 1H), 6.41 (dd, J=15.9, 7.8 Hz, 1H), 4.59 (d, J=5.6 Hz,2H), 4.45 (qd, J=9.0, 6.0 Hz, 2H), 4.12 (q, J=7.2 Hz, 1H); ESIMS m/z640.9 ([M−H]⁻).

Example 106 Preparation ofethyl(Z)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoate(AI76)

The title compound was made in accordance with the procedure disclosedin Example 88 and was isolated as a yellow viscous oil (416 mg, 23%):

¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=8.0 Hz, 1H), 7.40 (d, J=1.7 Hz,1H), 7.35 (s, 2H), 7.12 (dd, J=8.0, 1.7 Hz, 1H), 6.86 (d, J=11.4 Hz,1H), 6.23-5.91 (m, 1H), 4.42 (q, J=7.1 Hz, 2H), 4.33-4.10 (m, 1H), 1.42(t, J=7.2 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −69.34 (d, J=8.3 Hz); EIMSm/z 514.10 GMT); IR (thin film) 2983, 1727, 1247, 1204, 1116 cm⁻¹.

Example 107 Preparation of(Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoicacid (AI77)

To a stirred solution of (Z)-ethyl2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoate(360 mg, 0.70 mmol) in CH₃CN (1.0 mL) was added iodotrimethylsilane(0.28 mL, 2.8 mmol). The reaction mixture was heated to reflux for 20 h,allowed to cool to ambient temperature and partitioned between CH₂Cl₂and aq. 10% Na₂S₂O₃. Organic phase was washed once with aq. 10% Na₂S₂O₃and dried over MgSO₄ and concentrated in vacuo. Passing the materialthrough a silica plug with 10% EtOAc in hexanes, followed by 20% MeOH inCH₂Cl₂) as the eluting solvents afforded the title compound as a yellowfoam (143 mg, 42%): mp 54-64° C.; ¹H NMR (400 MHz, CDCl₃) δ 11.36 (s,1H), 7.99 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.30 (s, 2H), 7.14 (d, J=7.9Hz, 1H), 6.85 (d, J=11.4 Hz, 1H), 6.15 (t, J=10.9 Hz, 1H), 4.36-4.09 (m,1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −69.30.

Example 108 Preparation of(Z)-2-bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide(AC95)

To a stirred solution of(Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoicacid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg,0.51 mmol). The mixture was heated in a 50° C. oil bath for 1.5 h,treated with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride(109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h.After cooling to ambient temperature, the mixture was taken up in Et₂Oand washed twice with aq. 5% NaHSO₄ (2×) and once with sat. NaCl (1×).After dying over MgSO₄, concentration in vacuo and purification bymedium pressure chromatography on silica with EtOAc/Hexanes as theeluents, the title compound was obtained as a white foam (160 mg, 41%)mp 48-61° C.: ¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J=7.9 Hz, 1H),7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz,1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23(d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); ¹⁹F NMR (376 MHz,CDCl₃) δ −69.31, −72.3; EIMS m/z 626.9 ([M+1]⁺).

Example 109a Preparation of(E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide(AC114)

(E)-tert-Butyl4-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)piperidine-1-carboxylate(0.75 g, 1.11 mmol) was added to dioxane HCl (10 mL) at 0° C. and wasstirred for 18 h. The reaction mixture was concentrated under reducedpressure and triturated with diethylether to afford the compound as alight brown solid (0.6 g, 88%).

Example 109b Preparation of(E)-N-(1-acetylpiperidin-4-yl)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide(AC103)

To a stirred solution of(E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide(0.1 g, 0.16 mmol) in DCM (10.0 mL) was added triethylamine (0.046 mL,0.35 mmol) and stirred for 10 min. Then acetyl chloride (0.014, 0.18mmol) was added and stirred for 16 h at RT. The reaction mixture wasdiluted with DCM and washed with saturated NaHCO₃ solution and brinesolution. The combined DCM layer was dried over Na₂SO₄ and concentratedunder reduced pressure to afford crude compound. The crude compound waswashed with 5% diethyl ether/n-pentane to afford the title compound as awhite solid (0.054 g, 50%).

Example 110 Preparation of(E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N-(1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)benzamide(AC104)

To a stirred solution of 3,3,3-trifluoropropanoic acid (0.02 g, 0.16mmol) in DCM (10.0 mL),(E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide(0.1 g, 0.16 mmol), PYBOP (0.09 g, 0.17 mmol), and DIPEA (0.06 g, 0.48mmol) were added at RT. The reaction mixture was stirred at RT for 5 h.The reaction mixture was diluted with DCM. The combined DCM layer waswashed with 3N HCl and saturated NaHCO₃ solution, the separated DCMlayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford crude compound. The crude compound was purified bycolumn chromatography (SiO₂, 100-200 mesh; eluting with 2% methanol inDCM) to afford the title compound as a off white gummy material (0.035g, 29.%).

Example 111 Preparation of(E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide(AC105)

To a stirred solution of(E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide(0.1 g, 0.16 mmol) in THF (5.0 mL) was added triethylamine (0.06 mL,0.64 mmol) and stirred for 10 min. Then 2,2,2-trifluoroethyltriflluoromethanesulfonate (0.03, 0.16 mmol) was added and stirred for16 h at RT. The reaction mixture was diluted with ethyl acetate andwashed with saturated NaHCO₃ solution and brine solution. The combinedethyl acetate layer was dried over Na₂SO₄ and concentrated under reducedpressure to afford the title compound as a brown solid (0.05 g, 44%).

Example 112 Preparation of(E)-2-bromo-N-(1-methylpiperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide(AC106)

A solution of(E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide(0.1 g, 0.16 mmol), formaldehyde (30% in water) (0.1 mL, 0.16 mmol) andacetic acid (0.01 mL) in methanol (5.0 mL) was stirred at RT for 30 min.After that NaBH₃CN (0.01 g, 0.16 mmol) was added at 0° C. and thereaction was stirred for 8 h at RT. The solvent was removed underreduced pressure to obtain residue which was diluted with ethyl acetateand washed with saturated aq. NaHCO₃ solution and brine solution. Thecombined ethyl acetate layer was dried over Na₂SO₄ and concentratedunder reduced pressure to obtain a residue, which was triturated withdiethyl ether/pentane to afford the title compound as a pale yellowgummy material (0.06 g, 59%).

Example 113 Preparation of((E)-2-bromo-N-(1-(cyanomethyl)piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide(AC107)

To a stirred solution of(E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide(0.25 g, 0.43 mmol) in THF (10.0 mL) was added triethylamine (0.16 mL,1.29 mmol) and the reaction was stirred for 10 min. Then2-bromoacetonitrile (0.07, 0.65 mmol) was added and the reaction wasstirred for 8 h at RT. The reaction mixture was diluted with ethylacetate and washed with saturated brine solution. The combined ethylacetate layer was dried over Na₂SO₄ and concentrated under reducedpressure to afford the title compound as an off-white solid (0.125 g,46.8%).

Example 114 Preparation of(E)-2-bromo-N-(1-(oxetan-3-yl)piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide(AC108)

A solution of(E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide(0.2 g, 0.35 mmol), oxetan-3-one (0.027 g, 0.38 mmol) and acetic acid(0.01 mL) in methanol (5.0 mL) was stirred at RT for 30 min. After thatNaBH₃CN (0.022 g, 0.35 mmol) was added at 0° C. slowly lot wise over theperiod of 10 min and the reaction was stirred for 8 h at RT. The solventwas removed under reduced pressure to obtain a residue which was dilutedwith ethyl acetate and washed with saturated NaHCO₃ solution and brinesolution. The combined ethyl acetate layer was dried over Na₂SO₄ andconcentrated under reduced pressure to obtain a residue, which wastriturated with diethyl ether/pentane to afford the title compound as anoff-white solid (0.05 g, 23%).

Example 115 Preparation of(E)-2-bromo-N-(1-(2-hydroxyethyl)piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide(AC109)

To a stirred solution of(E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide(0.25 g, 0.43 mmol) in THF (10.0 mL) was added triethylamine (0.16 mL,1.29 mmol) and the reaction was stirred for 10 min. Then 2-chloroethanol(0.05, 0.65 mmol) was added and the reaction was stirred for 8 h at RT.The reaction mixture was diluted with ethyl acetate and washed withsaturated brine solution. The combined ethyl acetate layer was driedover Na₂SO₄ and concentrated under reduced pressure to afford the titlecompound as an off-white solid (0.09 g, 34%).

Example 116 Preparation of(E)-2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamido)aceticacid (AI78)

To a stirred solution of (E)-tert-butyl2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)acetate(440 mg, 0.734 mmol) in DCM (36.0 ml), was added TFA (4.0 mL) and thereaction mixture was stirred at RT for 1 h. The reaction mixture wasconcentrated under reduced pressure to obtain residue which was washedwith n-pentane to afford the title compound as an off-white solid (310mg, 78%): ¹H NMR (400 MHz, CDCl₃) δ 13.0 (s, 1H), 8.75 (t, J=5.7 Hz,1H), 7.93 (m, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 6.96(dd, J=15.3, 9.3 Hz, 1H), 6.78 (d, J=15.3 Hz, 1H), 4.83 (m, 1H), 3.90(d, J=5.7 Hz, 2H); ESIMS m/z 543.61 ([M+H]⁺); IR (thin film) 3429, 1635,1114, 772 cm⁻¹.

Example 117 Preparation of(E)-N-((6-chloropyridin-3-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-methylbenzothioamide(AC115)

To the stirred solution of(E)-N-((6-chloropyridin-3-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide(0.06 g, 0.117 mmol) in toluene (3 mL) was added Lawesson's reagent(0.14 g, 0.351 mmol) and the reaction was irradiated at 100° C. for 1 h,then cooled to RT and concentrated under reduced pressure to providecrude compound. The crude product was purified by preparative HPLC toafford the product as yellow color solid (0.03 g, 49%).

Example 118 Preparation of(E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-2-(trifluoromethoxy)benzamide(AC116)

Step 1. 2-(Trifluoromethoxy)-4-vinylbenzoic acid (AI79)

To a stirred solution of 4-bromo-2-(trifluoromethoxy)benzoic acid (1 g,3.67 mmol) in DMSO (20 mL) was added potassium vinyltrifluoroborate(1.47 g, 11.02 mmol) and potassium carbonate (1.52 g, 11.02 mmol). Thereaction mixture was degassed with argon for 30 minBistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride(0.13 g, 0.18 mmol) was added and the reaction mixture was heated to 80°C. for 1 h. The reaction mixture was diluted with water (100 mL),extracted with ethyl acetate (2×50 mL), washed with brine, and driedover Na₂SO₄. Concentration under reduced pressure furnished the crudecompound which was purified by flash column chromatography to afford theproduct as pale yellow gummy material (0.4 g, 47%): ¹H NMR (400 MHz,CDCl₃) δ 8.05 (d, J=8.1 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.35 (s, 1H),6.78 (dd, J=17.4.1, 11.1 Hz, 1H), 5.92 (d, J=17.4 Hz, 1H), 5.51 (d,J=10.8 Hz, 1H); ESIMS m/z 232.97 ([M+H]⁺).

Step 2.(E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(trifluoromethoxy)benzoicacid (AI80)

To a stirred solution of 2-(trifluoromethoxy)-4-vinylbenzoic acid (0.356g, 1.53 mmol) in 1N methyl pyrrolidine (5.0 mL) was added1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichloro 4-fluorobenzene (1.0 g,3.07 mmol), copper(I) chloride (CuCl; 0.03 g, 0.307 mmol) and 2,2bipyridyl (0.095 g, 0.614 mmol). The reaction mixture was stirred at150° C. for 1 h. After the reaction was complete by TLC, the reactionmixture was diluted with water (100 mL) and extracted with ethyl acetate(2×50 mL). The combined organic layers were washed with brine, driedover Na₂SO₄ and concentrated under reduced pressure to obtain the crudecompound which was purified by flash column chromatography to afford theproduct as pale yellow gummy material (0.3 g, 21%): ¹H NMR (400 MHz,CDCl₃) δ 8.08 (d, J=8.0 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.35 (s, 3H),6.63 (d, J=16.0 Hz, 1H), 6.50 (dd, J=16.0, 8.0 Hz, 1H), 4.15 (m, 1H);ESIMS m/z 474.81 ([M−H]⁻).

Step 3.(E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-2-(trifluoromethoxy)benzamide(AC116)

A mixture of(E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(trifluoromethoxy)benzoicacid (0.25 g, 0.52 mmol), 2-amino-N-(2,2,2-trifluoroethyl)acetamide(0.158 g, 0.62 mmol), PyBOP (0.40 g, 0.78 mmol) and DIPEA (0.134 g, 1.04mmol) in DCM (10.0 mL) were stirred at RT for 16 h. The reaction mixturewas diluted with water and extracted with DCM. The combined DCM layerwas washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure. Purification by flash column chromatography (SiO₂, 100-200mesh; eluting with 20% ethyl acetate/pet ether) afforded the titlecompound as a pale yellow gummy material (0.15 g, 47%).

Example 20 Preparation of 5-vinyl-2,3-dihydro-1H-inden-1-one (BI1)

To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.7mmol) in toluene were added vinylboronic anhydride pyridine complex(8.55 g, 35.54 mmol), Pd(PPh₃)₄ (0.1 g, 0.094 mmol), K₂CO₃ (22.88 g,165.83 mmol). The resultant reaction mixture was heated at reflux for 16h. The reaction mixture was cooled to 25° C. and filtered, and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with EtOAc and washed with H₂O and brine. The combined organicextracts were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The obtained residue was purified by flash columnchromatography (SiO₂, 5% EtOAc in petroleum ether) afforded the titlecompound as a solid (1.8 g, 48%): ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d,J=7.2 Hz, 1H), 7.49 (br s, 1H), 7.44 (d, J=7.2 Hz, 1H), 6.82 (m, 1H),5.90 (d, J=7.4 Hz, 1H), 5.42 (d, J=6.4 Hz, 1H), 3.20 (m, 2H), 2.70 (m,2H); ESIMS m/z 159.06 ([M+H]⁻).

The following compound was made in accordance with the proceduresdisclosed in Example 20.

6-Vinyl-3,4-dihydronaphthalen-1(2H)-one (BI2)

The product was isolated as an off-white solid (5 g, 48%): ¹H NMR (400MHz, DMSO-d₆) δ 7.85 (d, J=8.4 Hz, 1H), 7.48 (m, 2H), 6.82 (m, 1H), 6.02(d, J=7.4 Hz, 1H), 5.44 (d, J=6.4 Hz, 1H), 2.95 (m, 2H), 2.60 (m, 2H),2.00 (m, 2H); ESIMS m/z 173.14 ([M−H]⁻); IR (thin film) 1681 cm⁻¹.

Example 21 Preparation of(E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-one(BI3)

5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (4 g, 11.7mmol), 5-vinyl-2,3-dihydro-1H-inden-1-one (0.92 g, 5.8 mmol), CuCl(0.115 g, 1.171 mmol) and 2,2-bipyridyl (0.053 g, 0.34 mmol) in1,2-dichlorobenzene (25 mL) were heated at 180° C. for 16 h. Thereaction mixture was cooled to 25° C. and concentrated under reducedpressure. The residue was purified by flash column chromatography (SiO₂,5% EtOAc in petroleum ether) to afford the title compound as a liquid(1.28 g, 25%): ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=7.4 Hz, 1H), 7.52(m, 3H), 6.68 (d, J=7.4 Hz, 1H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m,2H), 2.75 (m, 2H); ESIMS m/z 419.14 ([M+H]⁻); IR (thin film) 1708.94,1113.60, 807.77 cm⁻¹.

The following compound was made in accordance with the proceduresdisclosed in Example 21.

(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2,3-dihydro-1H-inden-1-one(BI4)

The product was isolated as a brown semi-solid (1.2 g, 16%): ¹H NMR (400MHz, CDCl₃) δ 7.76 (d, J=7.4 Hz, 1H), 7.54 (m, 3H), 7.30 (s, 1H), 6.68(d, J=7.4 Hz, 1H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.75 (m,2H); ESIMS m/z 400.84 ([M−H]⁻); IR (thin film) 815, 1113, 1709 cm⁻¹.

(E)-6-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(21-1)-one(BI5)

The product was isolated as a pale yellow semi solid (1.2 g, 30%): ¹HNMR (400 MHz, CDCl₃) δ 8.20 (d, J=8.0 Hz, 1H), 7.42 (s, 2H), 7.35 (m,1H), 7.24 (m, 2H), 6.62 (d, J=16 Hz, 1H), 6.46 (m, 1H), 4.18 (m, 1H),2.95 (m, 2H), 2.65 (m, 2H), 2.19 (m, 2H); ESIMS m/z 432.94 ([M−H]⁻); IR(thin film) 1680, 1113, 808 cm⁻¹.

Example 22 Preparation of(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-fluoro-2,3-dihydro-1H-inden-1-one(BI6)

To a stirred solution of(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one(0.5 g, 1.24 mmol) in acetonitrile (20 mL), was added Selectfluor® (0.52g, 1.48 mmol) and the reaction was heated to reflux temperature for 16h. The reaction mixture was cooled to room temperature, concentratedunder reduced pressure and diluted with DCM. The solution was washedwith water and brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give the crude product which waspurified by flash column chromatography (SiO₂, 100-200 mesh; 15% EtOAcin petroleum ether) to afford the title compound as a pale yellow semisolid (0.1 g, 24%): ¹H NMR (400 MHz, CDCl₃) δ 7.80 (m, 1H), 7.48 (m,2H), 7.32 (m, 2H), 6.65 (d, J=16.0 Hz, 1H), 6.54 (dd, J=16.0, 8.0 Hz,1H), 5.38 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.32 (m, 1H); ESIMS m/z419.06 ([M−H]⁻); IR (thin film) 1728, 1114, 817 cm⁻¹.

Example 23 Preparation of(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-inden-1-amine(BC10)

To a stirred solution of(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one(0.15 g, 0.35 mmol) in DCE (10 mL), was added trifluoropropyl amine(0.048 g, 0.42 mmol) and sodium cyanoborohydride (0.055 g, 0.875 mmol)in cooling and the reaction mixture was stirred at room temperature for16 h. The reaction mixture was diluted with DCE, was washed with waterand brine and dried over anhydrous sodium sulfate. Concentration underreduced pressure gave the crude compound, which was purified by flashcolumn chromatography (SiO₂, 100-200 mesh; 10-15% EtOAc in petroleumether) to afford the title compound as a colorless gummy material (0.042g, 24%): ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.20 (m, 5H), 6.62 (d, J=16.0Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 5.83 (br, 1H), 5.52 (m, 1H),4.12 (m, 1H), 3.02 (m, 3H), 2.82 (m, 1H), 2.50 (m, 2H), 1.82 (m, 1H),1.42 (m, 1H); ESIMS m/z 497.98 ([m−H]⁻); IR (thin film) 3027, 1654, 815cm⁻¹.

Example 24 Preparation of6-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(2H)-oneoxime (BI5a)

To a stirred solution of((E)-6-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(2H)-one(0.4 g, 0.92 mmol) in EtOH (50 mL) were added hydroxylaminehydrochloride (0.128 g, 1.85 mmol) and sodium acetate (0.23 g, 2.77mmol), and the reaction mixture was heated at reflux for 3 h. Thereaction mixture was concentrated under reduced pressure, and theresidue was diluted with H₂O and extracted with EtOAc. The combinedorganic extracts were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give the crude compound, whichwas purified by flash column chromatography (SiO₂, 100-200 mesh; 10-15%EtOAc in petroleum ether). The title compound was isolated as a solid(0.3 g, 73%): mp 155-158° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J=8.4Hz, 1H), 7.41 (s, 2H), 7.24 (m, 1H), 7.17 (m, 1H), 6.57 (d, J=16 Hz,1H), 6.46 (dd, J=16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.82 (m, 4H), 2.04 (m,2H); ESIMS m/z 445.95 ([M−H]⁻).

Example 25 Preparation of(E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine(BI5b)

To a stirred solution of(E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-one(1 g, 2.39 mmol) in CH₃OH (10 mL) were added ammonium acetate (1.84 g,23.9 mmol) and sodium cyanoborohydride (NaCNBH₃; 0.44 g, 7.17 mmol,) andthe reaction mixture was heated at reflux for 16 h. The reaction mixturewas concentrated under reduced pressure, and the residue was dilutedwith H₂O and extracted with EtOAc. The combined organic extracts werewashed with H₂O and saturated aqueous sodium bicarbonate (satd aqNaHCO₃) solution, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure to afford the title compound as a liquid (500 mg,crude): ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (s, 2H), 7.40 (s, 1H), 7.30 (s,2H), 6.71 (s, 2H), 4.78 (m, 1H), 4.2 (m, 1H), 2.80 (m, 1H), 2.73 (m,1H), 1.60 (m, 2H); ESIMS m/z 419.02 ([M+H]⁺); IR (thin film) 2924, 1552,1112, 807 cm⁻¹.

The following compound was made in accordance with the proceduresdisclosed in Example 25.

(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2,3-dihydro-1H-inden-1-amine(BI7)

The product was isolated as a light brown gummy material, taken as suchto the next step (0.15 g, crude compound): ESIMS m/z 401.97 ([M−H]⁻).

(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-fluoro-2,3-dihydro-1H-inden-1-amine(BI8)

The product was isolated as a light brown gummy material, taken as suchto the next step (0.15 g, crude compound): ESIMS m/z 420.15 ([M−H]⁻).

(E)-6-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-1,2,3,4-tetrahydronaphthalen-1-amine(BI9)

The product was isolated as a pale yellow liquid (500 mg crude).

Example 26 Preparation of(E)-1-methyl-3-(5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-but-1-enyl)-2,3-dihydro-1H-inden-1-yl)thiourea(BC1)

To a stirred solution of(E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine(0.1 g, 0.23 mmol) in Et₂O (5 mL) was added methylisothiocyanate (0.026g, 0.35 mmol), and the mixture was stirred for 2 h at 25° C. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by flash column chromatography (SiO₂, 20% EtOAc inpetroleum ether). The title compound was isolated as a liquid (65 mg,50%): ¹H NMR (400 MHz, CDCl₃) δ 7.39 (s, 2H), 7.25-7.18 (m, 3H), 6.58(d, J=16.0 Hz, 1H), 6.30 (dd, J=16.0, 8.4 Hz, 1H), 5.91-5.70 (br, 2H),4.05 (m, 1H), 3.05-2.80 (m, 6H), 2.70 (m, 1H), 1.81 (m, 1H); ESIMS m/z492.17 ([M+H]⁺); IR (thin film) 3211, 1569, 1113, 806 cm⁻¹.

Compounds BC2-BC3 in Table 1 were made in accordance with the proceduresdisclosed in Example 26.

Example 27 Preparation of(E)-3,3,3-trifluoro-N-(5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-yl)propanamide(BC4)

To a stirred solution of(E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine(0.1 g, 0.23 mmol) in CH₂Cl₂ (10 mL) were added trifluoropropionic acid(0.044 g, 0.34 mmol), EDC.HCl (0.038 g, 0.35 mmol), HOBt.H₂O (0.07 g,0.46 mmol) and DIEA (0.074 g, 0.57 mmol), and the reaction mixture wasstirred for 16 h at 25° C. The reaction mixture was diluted with CH₂Cl₂and washed with H₂O. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The crude material was purified by flash column chromatography (SiO₂,15% EtOAc in petroleum ether) to afford the title compound as a liquid(65 mg, 65%): ¹H NMR (400 MHz, CDCl₃) δ 7.39 (s, 2H), 7.25-7.20 (m, 3H),6.34 (d, J=16.0 Hz, 1H), 6.30 (dd, J=16.0, 8.0 Hz, 1H), 5.81 (br, 1H),5.48 (m, 1H), 4.10 (m, 1H), 3.10 (m, 2H), 2.86-3.07 (m, 2H), 2.86 (m,1H), 1.81 (m, 1H); ESIMS m/z 529.02 ([M+H]⁺); IR (thin film) 3283, 1652,1241, 811 cm⁻¹.

Compounds BC5-BC9, BC11 in Table 1 were made in accordance with theprocedures disclosed in Example 27.

Example 28 Preparation of tert-butyl 5-vinylindoline-1-carboxylate(BI10)

Step 1. 5-Bromo-indoline (BI11)

To 5-Bromo-1H-indole (2.5 g, 12.82 mmol) in acetic acid (10.0 mL),NaCNBH₃ (2.38 g, 38.46 mmol) was added portion wise at 10° C. over theperiod of 20 min. After that the reaction mixture was stirred at RT for3 h. The reaction mixture was diluted with water and extracted withdiethyl ether. The organic layer was washed with saturated NaHCO₃, waterand brine solution. The combined ether layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford title compoundas a pale yellow semi-solid (1.8 g, 71%).

Step 2. tert-Butyl-5-bromoindoline-1-carboxylate (BI12)

To a stirred solution of 5-bromo-indoline (3.0 g, 15 mmol) inacetonitrile (100 ml), was added DMAP (0.185 g, 1.522 mmol) anddi-tert-butyl dicarbonate (3.98 g, 18.3 mmol) and the reaction wasstirred at RT for 16 h. The reaction mixture was concentrated on reducedpressure to obtain a residue which was diluted with diethyl ether andwashed with water and brine solution (2×). The combined ether layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford the crude product as a off-white solid, which was used in thenext step without further purification (3.0 g).

Step 3. tert-Butyl-5-vinylindoline-1-carboxylate (BI10)

A stirred solution of ten-butyl-5-bromoindoline-1-carboxylate (2.0 g,6.73 mmol), potassium vinyl trifluoroborate (2.6 g, 20.20 mmol) andK₂CO₃ (2.78 g, 20.2 mmol) in DMSO (50.0 mL) was degassed with argon for20 min at RT. PdCl₂(dppf) (0.49 g, 0.67 mmol) was added at RT, then thereaction mixture was heated to 100° C. for 3 h. The reaction mixture wascooled to RT and filtered through a celite bed under vacuum and washedwith diethyl ether. The reaction mixture was extracted with diethylether. The combined diethyl ether layer was dried over Na₂SO₄ andconcentrated under reduced pressure to afford crude product. The crudecompound was purified by column chromatography (SiO₂, 100-200 mesh;eluting with 2% ethyl acetate/petroleum ether) to afford the titlecompound as a off-white solid (1.2 g, 73%): Mp 85.5-88.6° C.; ¹H NMR(400 MHz, CDCl₃) δ 7.23 (m, 3H), 6.69 (dd, J=17.4, 10.8 Hz, 1H), 5.64(d, J=10.5 Hz, 1H), 5.13 (d, J=10.5 Hz, 1H), 4.00 (t, J=9.0 Hz, 2H),3.10 (t, J=9.0 Hz, 2H), 1.55 (bs, 9H).

Example 29 Preparation of (E)-tert-butyl5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indoline-1-carboxylate(BI13)

To a stirred solution of tert-butyl-5-vinylindoline-1-carboxylate (1.28g, 5.23 mmol) in 1,2-dichlorobenzene (10.0 mL), was added5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (3.4 g, 10mmol), CuCl (103 mg, 1.05 mmol) and 2,2-bipyridyl (0.326 g, 2.092 mmol)and the resultant reaction mixture was degassed with argon for 30 minand heated to 150° C. for 1 h. The reaction mixture was cooled to RT andfiltered and the filtrate was concentrated under reduced pressure. Thecrude compound was purified by column chromatography (SiO₂, 100-200mesh; 2% ethyl acetate/petroleum ether) to afford the title compound asa pale yellow gummy solid (0.3 g, 61%): ¹H NMR (400 MHz, CDCl₃) δ 7.34(d, J=6.0 Hz, 2H), 7.22 (s, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.52 (d, J=16.0Hz, 1H), 6.21 (dd, J=16.0, 7.6 Hz, 1H), 4.07 (m, 3H), 3.10 (t, J=8.4 Hz,2H), 1.55 (s, 9H); ESIMS m/z 433.79 ([M−H]⁻); IR (thin film) 1168, 858cm⁻¹.

Example 30 Preparation of(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indolin-1-amine(BI14)

Step 1.(E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline(BI15)

To a stirred solution of(E)-tert-butyl-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-carboxylate(0.2 g, 0.4 mmol) in DCM (10.0 mL) was added TFA (0.6 mL) and thereaction was stirred at RT for 2 h. The reaction mixture was dilutedwith DCM, washed with saturated aq NaHCO₃, water and brine solution. Theseparated DCM layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to afford the crude product as a light browngummy material which was used in the next step without furtherpurification (0.12 g): ¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J=6.4 Hz, 2H),7.21 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.49 (d,J=15.6 Hz, 1H), 6.21 (dd, J=15.6, 8.4 Hz, 1H), 4.07 (m, 1H), 3.61 (t,J=8.4 Hz, 2H), 3.05 (t, J=8.4 Hz, 2H); ESIMS m/z 389.89 ([M+H]⁺); IR(thin film) 3385, 1112, 816 cm⁻¹.

Step 2.5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-nitrosoindoline(BI16)

To(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline(0.2 g, 0.5 mmol) in concentrated HCl (5.0 ml) at 5° C., was addedslowly NaNO₂ in water and the reaction was allowed to stir at RT for 2h. The reaction mixture was diluted with DCM, and the DCM layer washedwith water and brine solution. The separated DCM layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford thecrude product as a pale yellow solid that was used in the next stepwithout further purification (0.2 g): ¹H NMR (400 MHz, CDCl₃) δ 7.33 (d,J=8.4 Hz, 1H), 7.39 (m, 4H), 6.61 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0,8.4 Hz, 1H), 4.07 (m, 3H), 3.23 (t, J=8.4 Hz, 2H); ESIMS m/z 418.82([M+H]⁺); IR (thin film) 1488, 1112, 860 cm⁻¹.

Step 3.(E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indolin-1-amine(BI14)

To(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-nitrosoindoline(0.1 g, 0.2 mmol) in methanol (10.0 mL) was added zinc powder (77.5 mg)and NH₄Cl (36.9 mg, 0.69 mmol) in water (2.0 mL). The reaction mixturewas stirred at RT for 3 h. The reaction mixture was diluted with DCM andthe DCM layer was washed with water and brine solution. The separatedDCM layer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford the crude compound, which was purified by columnchromatography (SiO₂, 100-200 mesh; eluting with 2% ethylacetate/petroleum ether) to afford the title compound as a light browngummy material (0.08 g): ESIMS m/z 404.86 ([M+H]⁺).

Example 31 Preparation of(E)-N-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indolin-1-yl)-3,3,3-trifluoropropanamide(BC12)

To a stirred solution of(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-amine(0.1 g, 0.247 mmol) in DCM (10.0 ml) was added 3,3,3-trifluoropropanoicacid (0.038 g, 0.297 mmol), PyBOP (0.192 g, 0.370 mmol) and DIEA (0.047g, 0.370 mmol) and the reaction was stirred at RT for 18 h. The reactionmixture was diluted with DCM, and the separated DCM layer dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford thecrude compound. The crude compound was purified by column chromatography(SiO₂, 100-200 mesh; 20-25% ethyl acetate/petroleum ether) to afford thetitle compound as a light brown gummy material (0.12 g, 33%): ¹H NMR(400 MHz, CDCl₃) δ 7.32, (d, J=6.0 Hz, 2H) 7.28 (m, 1H), 7.20 (d, J=8.0,1H), 7.14 (d, J=8.8, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.60 (m, 2H), 4.15 (m,1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); ESIMS m/z514.86 ([M+H]⁺); IR (thin film) 3428, 1112, 857 cm⁻¹.

Example 32 Preparation of tert-butyl-5-vinyl-1H-indole-1-carboxylate(BI17)

Step 1. 5-Vinyl-1H-indole (BI18)

A mixture of 5-bromo-1H-indole (2.5 g, 12.82 mmol), potassiumvinyltrifluoroborate (2.57 g, 19.2 mmol), Cs₂CO₃ (12.53 g, 38.46 mmol)and triphenylphosphine (201 mg, 0.769 mmol) in THF/water (9:1, 75 ml)was degassed with argon for 20 min, then charged with PdCl₂ (45.3 mg,0.256 mmol). The reaction mixture was heated to reflux for 16 h, thencooled to RT, filtered through celite bed and washed with ethyl acetate.The filtrate was again extracted with ethyl acetate, and the combinedorganic layer washed with water and brine, dried over Na₂SO₄ andconcentrated under reduced pressure to afford the crude compound. Thecrude compound was purified by column chromatography (SiO₂, 100-200mesh; 2% ethyl acetate/petroleum ether) to afford the title compound asa light brown gummy material (1.5 g, 83%): ¹H NMR (400 MHz, CDCl₃) δ8.20 (br, 1H), 7.68 (s, 1H), 7.45 (s, 2H), 7.21 (m, 1H), 6.90 (dd,J=16.0, 10.8 Hz, 1H), 6.55 (m, 1H), 5.75 (d, J=10.5 Hz, 1H), 5.21 (d,J=10.5 Hz, 1H); ESIMS m/z 142.05 ([M−H]⁻).

Step 2. tert-Butyl-5-vinyl-1H-indole-1-carboxylate (BI17)

To a stirred solution of 5-vinyl-1H-indole (0.7 g, 4.89 mmol) inacetonitrile (20 ml) was added DMAP (59.65 mg, 0.489 mmol) anddi-tert-butyl dicarbonate (1.38 g, 6.36 mmol), and the reaction wasstirred at RT for 3 h. The reaction mixture was concentrated underreduced pressure to obtain a residue which was diluted with DCM andwashed with water and brine solution. The combined DCM layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to affordthe crude compound. The crude compound was purified by columnchromatography (SiO₂, 100-200 mesh; 2% ethyl acetate/petroleum ether) toafford the title compound as an off-white semi-solid (0.7 g, 59%): ¹HNMR (400 MHz, CDCl₃) δ 8.15 (d, J=8.0 Hz, 1H), 7.60 (s, 2H), 7.30 (d,J=8.4 Hz, 1H), 7.21 (m, 1H), 6.90 (dd, J=16.0, 10.8 Hz, 1H), 6.59 (s,1H), 5.75 (d, J=10.5 Hz, 1H), 5.21 (d, J=10.5 Hz, 1H), 1.65 (s, 9H);ESIMS m/z 242.10 ([M−H]⁻); IR (thin film) 1630 cm⁻¹.

Example 33 Preparation of (E)-tert-butyl5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indole-1-carboxylate(BI19)

To a stirred solution of tert-butyl 5-vinyl-1H-indole-1-carboxylate(0.65 g, 2.67 mmol), in 1,2-dichlorobenzene (10.0 mL) was added5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (1.74 g,5.37 mmol), CuCl (53 mg, 0.537 mmol) and 2,2-bipyridyl (167 mg, 1.07mmol). The resultant reaction mixture was degassed with argon for 30 minand heated to 150° C. for 2 h. The reaction mixture was cooled to RT andfiltered, and the filtrate concentrated under reduced pressure. Thecrude compound was purified by column chromatography (SiO₂, 100-200mesh; 2% ethyl acetate/petroleum ether) to afford the title compound asa light brown gummy material (0.25 g, 10%): ¹H NMR (400 MHz, CDCl₃) δ8.20 (d, J=8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J=16.0 Hz,1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m,1H), 1.65 (s, 9H); ESIMS m/z 485.91 ([m−H]⁻); IR (thin film) 1165, 854cm⁻¹.

Example 34 Preparation of(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indole(BI20)

To a stirred solution of (E)-tert-butyl5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indole-1-carboxylate(0.2 g, 0.40 mmol) in DCM (10.0 mL) was added TFA (70 mg, 0.61 mmol) andthe reaction was stirred at RT for 2 h. The reaction mixture was dilutedwith DCM and washed with saturated NaHCO₃ solution, water and brinesolution. The separated DCM layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound as alight brown solid (0.2 g, 97%): mp 132.9-138.8° C.; ¹H NMR (400 MHz,CDCl₃) δ 11.19 (br, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m,3H), 6.69 (d, J=16.0 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0,8.0 Hz, 1H), 4.82 (m, 1H); ESIMS m/z 387.98 ([M+H]⁺).

Example 35 Preparation of 4-nitrophenyl2-((tert-butoxycarbonyl)amino)acetate (BI21)

To a stirred solution of 4-nitrophenol (1.0 g, 7.19 mmol) in DCM (20.0mL) was added N-Boc glycine (1.38 g, 7.91 mmol) and EDC HCl (2.05 g,10.785 mmol) and the reaction was stirred at RT for 24 h. The reactionmixture was diluted with DCM and washed with water and saturated brinesolution. The separated DCM layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound as alight brown gummy material that was used in the next step withoutfurther purification (1.1 g): ¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, J=9.2Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 5.07 (br, 1H), 4.20 (s, 2H), 1.47 (s,9H); ESIMS m/z 296.27 ([M+H]⁺).

Example 36 Preparation of(E)-tert-butyl(2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indol-1-yl)-2-oxoethyl)carbamate(BI22)

To a stirred solution of(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indole(0.1 g, 0.258 mmol) in acetonitrile (5.0 mL) was added 4-nitrophenyl2-(tert-butoxycarbonylamino) acetate (0.114 g, 0.387 mmol), potassiumfluoride (0.03 g, 0.516 mmol), 18-crown-6-ether (0.075 g, 0.283 mmol)and DIEA (0.0332 g, 0.258 mmol) and the reaction was stirred at RT for16 h. The reaction mixture was concentrated to obtain a residue whichwas diluted with DCM and washed with water and brine solution. Theseparated DCM layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to afford the crude title compound as a lightbrown gummy material which was used in the next step without furtherpurification (0.1 g): ESIMS m/z 545.23 ([M+H]⁺).

Example 37 Preparation of(E)-N-(2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indol-1-yl)-2-oxoethyl)-3,3,3-trifluoropropanamide(BC13)

Step 1.(E)-2-amino-1-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)ethanone(BI23)

To a stirred solution of (E)-tert-butyl2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)-2-oxoethylcarbamate(0.05 g, 0.09 mmol) in DCM (5.0 mL) was added TFA (0.01 mL) and thereaction was stirred at RT for 16 h. The reaction mixture was dilutedwith DCM and washed with saturated NaHCO₃ solution, water and brinesolution. The separated DCM layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the crude title compoundwhich was used in the next step without further purification (50 mg).

Step 2.(E)-N-(2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indol-1-yl)-2-oxoethyl)-3,3,3-trifluoropropanamide(BC13)

To a stirred solution of(E)-2-amino-1-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)ethanone (0.04 g, 0.09 mmol) in DCM (5.0 ml) was added3,3,3-trifluoropropanoic acid (17.5 mg, 0.136 mmol), PyBOP (70 mg, 0.135mmol) and DIEA (29 mg, 0.225 mmol) and the reaction was stirred at RTfor 16 h. The reaction mixture was diluted with DCM, and the DCM layerwas washed with water and saturated brine solution. The separated DCMlayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford the crude compound, which was purified by columnchromatography (SiO₂, 100-200 mesh; 10% ethyl acetate/petroleum ether)to afford the title compound as an off-white solid (30 mg, 60%): mp121-126° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.33 (br, 1H), 7.59 (s, 1H), 7.45(m, 4H), 6.72 (d, J=3.6 Hz, 3H), 6.39 (m, 1H), 4.71 (t, J=7.2 Hz, 2H),4.15 (m, 1H), 3.51 (m, 1H), 3.28 (m, 1H); ESIMS m/z 553.06 ([M−H]⁻).

Example 38 Preparation of ethyl2-(1-oxo-6-vinylphthalazin-2(1H)-yl)acetate (BI24)

Step 1. 5-Bromo-3-hydroxyisoindoline-1-one (BI25)

A mixture of Zn powder (1.73 g, 26.154 mmol), copper (II) sulfatepentahydrate (0.02 g, 0.08 mmol) and 2M aq NaOH (27 mL) were cooled to0° C. 5-Bromoisoindoline-1,3-dione (5 g, 22 mmol) was added at the sametemperature over the period of 30 min. The reaction mixture was stirredat 0° C. for 30 min and 3 h at RT. The reaction mixture was filtered andthe filtrate was neutralized with concentrated HCl. The reaction mixturewas diluted with ethanol and extracted with ethyl acetate. The combinedethyl acetate layer was dried over Na₂SO₄ and concentrated under reducedpressure to afford the crude title compound as a brown solid, which wasused in the next step without further purification (1.3 g): mp 258-261°C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (br, 1H), 7.81 (m, 2H), 7.69 (m,1H), 6.44 (m, 1H), 5.88 (d, J=9.3 Hz, 1H); ESIMS m/z 225.83 ([M−H]⁻); IR(thin film) 1684, 3246, 606 cm⁻¹.

Step 2. 6-Bromophthalazine-1(2H)-one (BI26)

To a stirred solution of 5-bromo-3-hydroxyisoindoline-1-one (1.0 g, 4.40mmol) in water, was added hydrazine hydrate (0.45 g, 8.80 mmol) andheated to 95° C. for 5 h. The reaction mixture was cooled to RT,filtered and washed with diethyl ether and pentane (1:1) to afford thetitle compound as a white solid that was used in the next step withoutfurther purification (0.5 g): ESIMS m/z 225.15 ([M+H]⁺).

Step 3. 6-vinylphthalazine-1(2H)-one (BI27)

A solution of 6-bromophthalazine-1(2H)-one (0.25 g, 1.11 mmol),potassium vinyl trifluoroborate (0.446 g, 3.33 mmol) and K₂CO₃ (0.46 g,3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at RT.PdCl₂(dppf) (0.04 g, 0.055 mmol) was added at RT, and the reactionmixture was heated to 80° C. for 2 h. The reaction mixture was cooled toRT and filtered through celite bed under vacuum and washed with ethylacetate. The reaction mixture was extracted with ethyl acetate and thecombined ethyl acetate layer dried over Na₂SO₄ and concentrated underreduced pressure to afford the crude product. The crude compound waspurified by column chromatography (SiO₂, 100-200 mesh; 50% ethylacetate/petroleum ether) to afford the title compound as a brown solid(0.12 g, 63%): ¹H NMR (400 MHz, DMSO-d₆) δ 13.61 (br, 1H), 8.33 (m, 1H),8.19 (m, 1H), 8.01 (m, 2H), 6.97 (m, 1H), 6.15 (m, 1H), 5.56 (d, J=10.8Hz, 1H); ESIMS m/z 172.93 ([M+H]⁺); IR (thin film) 1748, 1655, 3241cm⁻¹.

Step 4. Ethyl-2-(1-oxo-6-vinylphthalazine-2(1H)-yl acetate (BI24)

To a stirred solution of 6-vinylphthalazine-1(2H)-one (0.5 g, 2.90 mmol)in DMF (5.0 mL) was added Cs₂CO₃ (0.94 g, 2.90 mmol) and the reactionwas stirred for 10 min Ethyl bromoacetate (0.48 g, 2.90 mmol) was addedto the reaction mixture at RT and the reaction was stirred for 8 h atRT. The reaction mixture was diluted and extracted with ethyl acetate,and the ethyl acetate layer was washed with water and brine solution(2×). The separated ethyl acetate layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford crude product. Thecrude compound was purified by column chromatography (SiO₂, 100-200mesh; 25% ethyl acetate/petroleum ether) to afford the title compound asa brown solid (0.34 g, 45%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (m, 1H),8.24 (m, 1H), 8.04 (m, 2H), 7.01 (m, 1H), 6.17 (d, J=2.1 Hz, 1H), 5.56(d, J=10.8 Hz, 1H), 4.92 (s, 2H), 4.19 (m, 2H), 1.23 (m, 3H). ESIMS m/z259.10 ([M+H]⁺); IR (thin film) 1750, 1660 cm⁻¹.

Example 39 Preparation of (E)-ethyl2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1-oxophthalazin-2(1H)-yl)acetate(BI28)

To a stirred solution of ethyl-2-(1-oxo-6-vinylphthalazine-2(1H)-ylacetate (0.07 g, 0.27 mmol) in 1,2-dichlorobenzene (1.0 mL) was added5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2fluorobenzene (0.17 g,0.54 mmol), CuCl (0.005 g, 0.05 mmol) and 2,2-bipyridyl (0.016 g, 0.10mmol) and the resultant reaction mixture was degassed with argon for 30min and heated to 180° C. for 12 h. The reaction mixture was cooled toRT and filtered and the filtrated was concentrated under reducedpressure. The crude compound was purified by column chromatography(SiO₂, 100-200 mesh; 10-15% ethyl acetate/petroleum ether) to afford thetitle compound as a brown solid (40 mg, 29%): ¹H NMR (400 MHz, DMSO-d₆)δ 8.40 (d, J=8.4 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.65 (s, 1H), 7.37 (d,J=6.3 Hz, 2H), 6.76 (d, J=16.0 Hz, 1H), 6.59 (dd, J=16.0, 8.0 Hz, 1H),4.96 (s, 2H), 4.29 (m, 3H), 1.31 (t, J=7.2 Hz, 3H); ESIMS m/z 503.0([M+H]⁺); IR (thin film) 1660, 1114, 817 cm⁻¹.

Example 40 Preparation of(E)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1-oxophthalazin-2(1H)-yl)aceticacid (BI29)

A solution of(E)-ethyl-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-oxophthalazin-2(1H)-yl)acetate (0.04 g, 0.07 mmol) in HCl (0.5 mL) and acetic acid (0.5 mL) washeated to 100° C. for 3 h. The solvent was removed under reducedpressure and the residue diluted with water. The aqueous layer wasextracted with ethyl acetate and the separated ethyl acetate layer driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to affordthe crude compound. The crude compound was triturated with diethylether-pentane mixture to afford the title compound as a brown solid(0.03 g): ¹H NMR (400 MHz, DMSO-d₆) δ 13.0 (br s, 1H), 8.43 (m, 1H),8.23 (d, J=8.1 Hz, 1H), 8.14 (m, 2H), 7.91 (m, 2H), 7.16 (dd, J=16.0,8.0 Hz, 1H), 6.99 (d, J=16.0 Hz, 1H), 4.96 (m, 3H); ESIMS m/z 473.0([M−H]⁻); IR (thin film) 1629, 1168, 817 cm⁻¹.

Example 41 Preparation of(E)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1-oxophthalazin-2(1H)-yl)-N-(2,2,2-trifluoroethyl)acetamide(BC14)

To a stirred solution of(E)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-oxophthalazin-2(1H)-yl)aceticacid (0.15 g, 0.31 mmol) in DCM (20.0 ml) was added2,2,2,-trifluoroethanamine (0.03 g, 0.31 mmol), PyBOP (0.17 g, 0.34mmol) and DIEA (0.15 ml, 0.93 mmol) at RT, and the reaction was stirredfor 18 h. The reaction mixture was diluted with DCM and washed with 3NHCl (2×20 mL), NaHCO₃ (2×20 mL) and brine solution (2×). The separatedDCM layer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford the crude compound. The crude compound was purifiedby column chromatography (SiO₂, 100-200 mesh; 20-25% ethylacetate/petroleum ether) to afford the title compound as a brown solid(0.11 g): mp 172-175° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.83 (t, J=6.6 Hz,1H), 8.42 (t, J=14.7 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.13 (t, J=6.3 Hz,1H), 7.98-7.86 (m, 2H), 7.16-7.07 (m, 1H), 7.01-6.93 (m, 1H), 4.96-4.81(m, 3H), 4.00-3.88 (m, 2H); ESIMS m/z 554.0 ([M−H]⁻).

Example 42 Preparation of 2-(4-vinylbenzyl)isoindoline-1,3-dione (CI1)

To a stirred solution of 1-(chloromethyl)-4-vinylbenzene (10 g, 66 mmol)in DMF (100 mL) was added potassium phthalimide (13.3 g, 72.1 mmol), andthe resultant reaction mixture was heated at 70° C. for 16 h. Thereaction mixture was diluted with H₂O and extracted with CHCl₃. Thecombined CHCl₃ layer was washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. Recrystallization from CH₃OHafforded the title compound as an off-white solid (8 g, 46%): ¹H NMR(400 MHz, CDCl₃) δ 7.83 (m, 2H), 7.71 (m, 2H), 7.39 (m, 4H), 6.65 (dd,J=17.6, 10.8 Hz, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.21 (d, J=10.8 Hz, 1H),4.82 (s, 2H); GCMS m/z 263.2 ([M]⁺); IR (thin film) 3420, 1133, 718cm⁻¹.

Example 43 Preparation of(E)-2-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione(CI2)

Using the procedure of Example 10 with2-(4-vinylbenzyl)isoindoline-1,3-dione and1-(1-bromoethyl)-3,5-dichlorobenzene as the starting materials, thetitle compound was isolated as an off-white solid (0.3 g, 40-50%): mp142-145° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.86 (m, 2H), 7.74 (m, 2H), 7.42(m, 2H), 7.36 (m, 3H), 7.27 (m, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.32 (dd,J=16.0, 8.0 Hz, 1H), 4.82 (s, 2H), 4.05 (m, 1H); ESIMS m/z 488.17([m−H]⁻).

The following compound was made in accordance with the proceduresdisclosed in Example 43.

(E)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)isoindoline-1,3-dione(CI3)

The title compound was isolated as an off white solid (0.3 g, 56%): mp145-146° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.86 (m, 2H), 7.74 (m, 2H),7.42-7.31 (m, 6H), 6.58 (d, J=16.0 Hz, 1H), 6.53 (dd, J=16.0, 8.0 Hz,1H), 4.82 (s, 2H), 4.05 (m, 1H); ESIMS m/z 522.2 ([M−H]⁻); IR (thinfilm) 1716, 1110, 712 cm⁻¹.

Prophetically, compounds CI4-CI5 (Table 1) could be made in accordancewith the procedures disclosed in Example 43.

Example 44 Preparation of(E)-(4-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine(CI6)

To a stirred solution of(E)-2-(4-(3-(3,5-dichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3-dione(1.2 g, 2.45 mmol) in EtOH was added hydrazine hydrate (0.61 g, 12mmol), and the resultant reaction mixture was heated at 90° C. for 1 h.The reaction mixture was filtered, and the filtrate was concentrated.The residue was dissolved in CH₂Cl₂, washed with brine, dried overNa₂SO₄, and concentrated under reduced pressure to afford the crudetitle compound as a gummy liquid (0.9 g) which was used without furtherpurification.

The following compounds were made in accordance with the proceduresdisclosed in Example 44.

(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)methanamine(CI7)

The title compound was isolated and used without further purification.

Prophetically, compounds CI8-CI9 (Table 1) could be made in accordancewith the procedures disclosed in Example 44.

Example 45 Preparation of 4-(bromomethyl)-3-chlorobenzonitrile (CI10)

To a stirred solution of 3-chloro-4-methylbenzonitrile (5 g, 25.4 mmol)in carbon tetrachloride (CCl₄; 50 mL) under an argon atmosphere wasadded NBS (5.16 g, 29 mmol), and the mixture was degassed for 30 min. Tothis was added azobisisobutyronitrile (AIBN; 0.3 g, 1.8 mmol), and theresultant reaction mixture was heated at reflux for 4 h. The reactionmixture was cooled to ambient temperature, washed with H₂O, andextracted with CH₂Cl₂. The combined CH₂Cl₂ layer was washed with brine,dried over Na₂SO₄, and concentrated under reduced pressure. The crudecompound was purified by flash column chromatography (SiO₂, 100-200mesh; 5% EtOAc in n-Hexane) to afford the title compound as a whitesolid (4.8 g, 68%): mp 87-88° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.71 (s,1H), 7.59 (s, 2H), 4.60 (s, 2H); ESIMS m/z 229.77 ([M+H]⁺); IR (thinfilm) 2235, 752, 621 cm⁻¹.

The following compounds were made in accordance with the proceduresdisclosed in Example 45.

4-(Bromomethyl)-3-(trifluoromethyl)benzonitrile (CI11)

The title compound was isolated as an off-white gummy material (5 g,66%): ¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.86 (d, J=8.0 Hz, 1H),7.76 (d, J=8.0 Hz, 1H), 4.62 (s, 2H); ESIMS m/z 262.11 ([M−H]⁻); IR(thin film) 2236, 1132, 617 cm⁻¹.

3-Bromo-4-(bromomethyl)benzonitrile (CI12)

The title compound was isolated as an off-white solid (5 g, 67%): mp82-83° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 7.61 (m, 2H), 4.62(s, 2H); EIMS m/z 272.90; IR (thin film) 2229, 618 cm⁻¹.

4-(Bromomethyl)-3-fluorobenzonitrile (CI13)

The title compound was isolated as an off-white solid (2 g, 60%): mp79-81° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.54 (t, J=8.0 Hz, 1H), 7.48 (dd,J=8.0 Hz, 8.0, 1H), 7.38 (dd, J=5 Hz, 1H), 4.5 (s, 2H); EIMS m/z 215.

Example 46 Preparation of 4-(bromomethyl)-3-chlorobenzaldehyde (CI14)

To a stirred solution of 4-(bromomethyl)-3-chlorobenzonitrile (4.8 g, 17mmol) in toluene (50 mL) at 0° C. was added dropwise diisobutylaluminumhydride (DIBAL-H, 1.0 M solution in toluene; 23.9 mL), and the reactionmixture was stirred at 0° C. for 1 h. 10 M HCl in H₂O (5 mL) was addeduntil the reaction mixture turned to a white slurry and then additional1 N HCl (20 mL) was added. The organic layer was collected and theaqueous layer was extracted with CHCl₃. The combined organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by flash column chromatography (SiO₂, 100-200mesh; 5% EtOAc in n-Hexane) to afford the title compound as a whitesolid (3.8 g, 80%): mp 64-66° C.; ¹H NMR (400 MHz, CDCl₃) δ 10.00 (s,1H), 7.92 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.60(s, 2H); ESIMS m/z 232.78 ([M+H]⁺).

The following compounds were made in accordance with the proceduresdisclosed in Example 46.

4-(Bromomethyl)-3-(trifluoromethyl)benzaldehyde (CI15)

The title compound was isolated as a pale yellow low-melting solid (5 g,60%): ¹H NMR (400 MHz, CDCl₃) δ 10.09 (s, 1H), 8.19 (s, 1H), 8.09 (m,1H), 7.81 (m, 1H), 4.61 (s, 2H); ESIMS m/z 265.04 ([M−H]⁻); IR (thinfilm) 1709, 1126, 649 cm⁻¹.

3-Bromo-4-(bromomethyl)benzaldehyde (CI16)

The title compound was isolated as a pale yellow solid (5 g, 62%): mp94-95° C.; ¹H NMR (400 MHz, CDCl₃) δ 9.96 (s, 1H), 8.05 (s, 1H), 7.81(d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 4.60 (s, 2H); EIMS m/z275.90.

4-(Bromomethyl)-3-fluorobenzaldehyde (CI17)

The title compound was isolated as an off-white solid (5 g, 61%): mp43-45° C.; ¹H NMR (400 MHz, CDCl₃) δ 9.1 (s, 1H), 7.54 (t, J=8 Hz, 1H),7.48 (d, J=8 Hz, 1H), 7.38 (d, J=5 Hz, 1H), 4.5 (s, 2H); EIMS m/z 216.

Example 47 Preparation of3-chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (CI18)

To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (3.8 g, 14mmol) in DMF (40 mL) was added potassium pthalimide (3.54 g, 19.14mmol), and the mixture was heated at 60° C. for 6 h. The reactionmixture was cooled to ambient temperature and diluted with H₂O (100 mL).The solid obtained was separated by filtration and dried under vacuum toafford the title compound as a white solid (2.8 g, 60%): mp 123-126° C.;¹H NMR (400 MHz, CDCl₃) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91 (m, 3H), 7.80(m, 2H), 7.20 (m, 1H), 5.05 (s, 2H); ESIMS m/z 298.03 ([M−H]⁻).

The following compounds were made in accordance with the proceduresdisclosed in Example 47.

4-((1,3-Dioxoisoindolin-2-yl)-3-(trifluoromethyl)benzaldehyde (CI19)

The title compound was isolated as an off white solid (1 g, 62%): mp142-143° C.; ¹H NMR (400 MHz, CDCl₃) δ 10.05 (s, 1H), 8.15 (s, 1H), 7.91(m, 2H), 7.80 (m, 3H), 7.27 (m, 1H), 5.19 (s, 2H); ESIMS m/z 332.03([M−H]⁻).

3-Bromo-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (CI20)

The title compound was isolated as an off-white solid (0.5 g, 64%): mp159-161° C.; ¹H NMR (400 MHz, CDCl₃) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91(m, 3H), 7.80 (m, 2H), 7.20 (m, 1H), 5.05 (s, 2H); ESIMS m/z 314.00([M-CHO]⁻).

4-((1,3-Dioxoisoindolin-2-yl)-3-fluorobenzaldehyde (CI21)

The title compound was isolated as a white solid (2 g, 60%): mp 154-156°C.; ¹H NMR (400 MHz, CDCl₃) δ 9.95 (s, 1H), 7.9 (m, 2H), 7.75 (m, 2H),7.6 (m, 2H), 7.5 (t, J=7.6 Hz, 1H), 5.05 (s, 2H); EIMS m/z 283.1.

Example 48 Preparation of2-(2-chloro-4-vinylbenzyl)isoindoline-1,3-dione (CI22)

To a stirred solution of3-chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (2.8 g, 8.2mmol) in 1,4-dioxane (30 mL) were added K₂CO₃ (1.68 g, 12.24 mmol) andmethyl triphenyl phosphonium bromide (4.37 g, 12.24 mmol) at ambienttemperature. Then the resultant reaction mixture was heated at 100° C.for 18 h. After the reaction was deemed complete by TLC, the reactionmixture was cooled to ambient temperature and filtered, and the obtainedfiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography (SiO₂, 100-200 mesh; 20% EtOAc inn-Hexane) to afford the title compound as a white solid (1.94 g, 70%):mp 141-143° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.85 (m, 2H), 7.70 (m, 2H),7.41 (m, 1H), 7.21 (m, 2H), 6.71 (dd, J=17.6, 10.8 Hz, 1H), 5.72 (d,J=17.6 Hz, 1H), 5.23 (d, J=10.8 Hz, 1H), 4.92 (s, 2H); ESIMS m/z 298.10([M−H]⁻).

The following compounds were made in accordance with the proceduresdisclosed in Example 48.

2-(2-(Trifluoromethyl)-4-vinylbenzyl)isoindoline-1,3-dione (CI23)

The title compound was isolated as a light brown solid (0.5 g, 60%): mp134-135° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.71(s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.65 (m, 1H),5.80 (d, J=17.8 Hz, 1H), 5.19 (d, J=10.8 Hz, 1H), 5.09 (s, 2H); ESIMSm/z 332.10 ([M+H]⁺).

2-(2-Bromo-4-vinylbenzyl)isoindoline-1,3-dione (CI24)

The title compound was isolated as a off white solid (0.5 g, 62%): mp126-128° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.62(s, 1H), 7.21 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.62 (m, 1H), 5.72 (d,J=17.8 Hz, 1H), 5.15 (d, J=10.8 Hz, 1H), 4.95 (s, 2H); EIMS m/z 341.10.

2-(2-Fluoro-4-vinylbenzyl)isoindoline-1,3-dione (CI25)

The title compound was isolated as a white solid (0.5 g, 61%): mp140-142° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.85 (m, 2H), 7.72 (m, 2H), 7.25(m, 1H), 7.11 (m, 2H), 6.63 (m, 1H), 5.80 (d, J=17.6 Hz, 1H), 5.28 (d,J=10.8 Hz, 1H), 4.92 (s, 2H); EIMS m/z 282.08.

Example 49 Preparation of(E)-2-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione(CI26)

To a stirred solution of 2-(2-chloro-4-vinylbenzyl)isoindoline-1,3-dione(2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL) were added1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (3.48 g, 11.36mmol), CuCl (112 mg, 1.13 mmol) and 2,2-bipyridyl (0.35 g). Theresultant reaction mixture was degassed with argon for 30 min and thenwas stirred at 180° C. for 24 h. After the reaction was deemed completeby TLC, the reaction mixture was cooled to ambient temperature andfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography (SiO₂, 100-200 mesh; 25-30%EtOAc in n-hexane) to afford the title compound as solid (1.3 g, 50%):mp 141-143° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.92 (m, 2H), 7.79 (m, 2H),7.42 (m, 2H), 7.24 (m, 2H), 7.20 (m, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.34(dd, J=16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.10 (m, 1H); ESIMS m/z 524.07([M+H]⁺).

The following compounds were made in accordance with the proceduresdisclosed in Example 49.

(E)-2-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)isoindoline-1,3-dione(CI27)

The title compound was isolated as a pale white solid (0.2 g, 55%): mp128-129° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42(m, 3H), 7.22 (m, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0Hz, 1H), 5.00 (s, 2H), 4.05 (m, 1H); ESIMS m/z 557.99 ([M+H]⁺).

(E)-2-(2-Chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione(CI28)

The title compound was isolated as a off white solid (0.2 g, 54%): mp177-180° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.90 (m, 2H), 7.77 (m, 2H), 7.42(s, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.21 (m, 2H), 6.52 (d, J=16.0 Hz, 1H),6.32 (dd, J=16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.05 (m, 1H); ESIMS m/z540.08 ([M−H]⁻); IR (thin film) 1716 cm⁻¹.

(E)-2-(2-Chloro-4-(3-(3,4-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione(CI29)

The title compound was isolated as an off-white solid (0.2 g, 59%): ¹HNMR (400 MHz, CDCl₃) δ 7.89 (m, 2H), 7.76 (m, 2H), 7.47 (m, 3H), 7.21(m, 3H), 6.50 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 7.6 Hz, 1H), 4.97(s, 2H), 4.11 (m, 1H); ESIMS m/z 522.27 ([M−H]⁻); IR (thin film) 3064,1717, 1111, 715 cm⁻¹.

(E)-2-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)-benzyl)isoindoline-1,3-dione(CI30)

The title compound was isolated as an off-white solid (0.2 g, 54%): mp141-142° C.; ¹H NMR (400 MHz, CDCl₃) 7.94 (m, 2H), 7.80 (m, 2H), 7.69(s, 1H), 7.44 (m, 1H), 7.38 (m, 1H), 7.24 (m, 2H), 7.19 (m, 1H), 6.60(d, J=16.0 Hz, 1H), 6.39 (dd, J=16.0, 7.6 Hz, 1H), 5.10 (s, 2H), 4.11(m, 1H); ESIMS m/z 556.00 ([M−H]⁻).

(E)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)-benzyl)isoindoline-1,3-dione(CI31)

The title compound was isolated as an off-white solid (0.2 g, 56%): mp130-132° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.94 (m, 2H), 7.80 (m, 2H), 7.69(s, 1H), 7.44 (m, 3H), 7.19 (m, 1H), 6.61 (d, J=16.0 Hz, 1H), 6.38 (dd,J=16.0, 7.6 Hz, 1H), 5.10 (s, 2H), 4.12 (m, 1H); ESIMS m/z 589.57([M−2H]⁻).

(E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3-dione(CI32)

The title compound was isolated as a pale yellow solid (0.2 g, 55%): mp160-162° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.62(s, 1H), 7.39 (s, 2H), 7.24 (m, 1H), 7.16 (m, 1H), 6.52 (d, J=16.0 Hz,1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 4.98 (s, 2H), 4.12 (m, 1H); ESIMSm/z 599.78 ([M−H]⁻).

(E)-2-(2-Fluoro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3-dione(CI33)

The title compound was isolated as an off-white solid (0.2 g, 55%): mp72-74° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.88 (m, 2H), 7.74 (m, 2H), 7.38(s, 2H), 7.34 (m, 1H), 7.18 (m, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.32 (dd,J=16.0, 8.0 Hz, 1H), 4.91 (s, 2H), 4.08 (m, 1H); ESIMS m/z 539.89([M−H]⁻¹); IR (thin film) 1773 cm⁻¹.

Prophetically, compounds CI34-CI41 (Table 1) could be made in accordancewith the procedures disclosed in Example 49.

Example 50 Preparation of(E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine(CI42)

To a stirred solution of(E)-2-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione(0.4 g, 0.76 mmol) in EtOH was added hydrazine hydrate (0.38 g, 7.6mmol), and the resultant reaction mixture was heated at 80° C. for 2 h.The reaction mixture was filtered, and the filtrate was concentrated.The residue was dissolved in CH₂Cl₂, washed with brine, dried overNa₂SO₄, and concentrated under reduced pressure to afford the titlecompound as a gummy liquid (0.3 g), which was carried on to the nextstep without further purification.

The following compounds were made in accordance with the proceduresdisclosed in Example 50.

(E)-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine(CI43)

The product obtained in this reaction was carried on to the next stepwithout further purification.

(E)-(2-Chloro-4-(3-(3,4-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-methanamine(CI44)

The product obtained in this reaction was carried on to the next stepwithout further purification: ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J=8.4Hz, 2H), 7.39 (m, 2H), 7.23 (m, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.38 (dd,J=16.0, 7.6 Hz, 1H), 4.12 (m, 1H), 3.90 (s, 2H); ESIMS m/z 391.90([M−H]⁻); IR (thin film) 3370, 3280, 1111, 817 cm⁻¹.

(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)-phenyl)methanamine(CI45)

The title compound was isolated as a gummy material. The productobtained in this reaction was carried on to the next step withoutfurther purification.

(E)-(2-Bromo-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-methanamine(CI46)

The title compound was isolated as a gummy material: The productobtained in this reaction was carried on to the next step withoutfurther purification.

(E)-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine(CI47)

The title compound was isolated as a gummy material. The productobtained in this reaction was carried on to the next step withoutfurther purification.

(E)-(2-Fluoro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine(CI48)

The title compound was isolated as a gummy material: ¹H NMR (400 MHz,CDCl₃) δ 7.40 (s, 2H), 7.33 (t, J=7.6 Hz, 1H), 7.13 (m, 2H), 6.56 (d,J=16.0 Hz, 1H), 6.33 (dd, J=16.0, 7.6 Hz, 1H), 4.08 (m, 1H), 3.90 (s,2H); ESIMS m/z 413.84 ([M+H]⁺); IR (thin film) 3368, 3274, 1114, 808cm⁻¹.

Prophetically, compounds CI49-CI57 (Table 1) could be made in accordancewith the procedures disclosed in Example 50.

Example 51 Preparation of3-chloro-4-((pyridin-2-ylamino)methyl)benzaldehyde (CI58)

To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (2 g, 9mmol) in N,N-dimethylacetamide (DMA; 20 mL) was added K₂CO₃ (2.36 g,17.16 mmol) and 2-aminopyridine (0.84 g, 8.58 mmol), and the reactionmixture was stirred at ambient temperature for 4 h. The reaction mixturewas diluted with H₂O and extracted with EtOAc. The combined organiclayer was washed with brine, dried over Na₂SO₄, and concentrated underreduced pressure. The residue was purified by flash columnchromatography (SiO₂, 100-200 mesh; 20% EtOAc in n-Hexane) to afford thetitle compound as off-white solid (1.05 g, 50%): mp 122-123° C.; ¹H NMR(400 MHz, CDCl₃) δ 9.94 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.72 (d,J=4.8 Hz, 1H), 7.62 (d, J=5.7 Hz, 1H), 7.4 (m, 1H), 6.64 (d, J=3.9 Hz,1H), 6.38 (d, J=6.3 Hz, 1H), 5.04 (br s, 1H), 4.71 (s, 2H); ESIMS m/z246.97 ([M+H]⁺).

Example 52 Preparation of N-(2-chloro-4-vinylbenzyl)pyridin-2-amine(CI59)

To a stirred solution of3-chloro-4-((pyridin-2-ylamino)methyl)benzaldehyde (1 g, 4. mmol) in1,4-dioxane (20 mL) were added K₂CO₃ (0.84 g, 6.09 mmol) and methyltriphenyl phosphonium bromide (2.17 g, 6.09 mmol) at ambienttemperature. Then the resultant reaction mixture was heated at 100° C.for 18 h. After the reaction was deemed complete by TLC, the reactionmixture was cooled to ambient temperature and filtered, and the obtainedfiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography (SiO₂, 100-200 mesh; 10% EtOAc inn-Hexane) to afford the title compound as a white solid (0.5 g, 50%): mp119-121° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.42-7.40 (m, 3H),7.26 (s, 1H), 6.66 (m, 2H), 6.36 (d, J=6.3 Hz, 1H), 5.75 (d, J=13.2 Hz,1H), 4.92 (br s, 1H), 4.60 (s, 2H); ESIMS m/z 245.05 ([M+H]⁺).

Example 53 Preparation of ethyl2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (CI60)

Ethyl 2-(diphenylmethyleneamino)acetate (10.2 g, 38.2 mmol) was added tosodium hydride (NaH; 3.18 g, 133.52 mmol) in DMF (50 mL) at 0° C., andthe mixture was stirred for 30 min. To this was added5-bromo-2,3-dichloropyridine (12.9 g, 57.23 mmol), and the reactionmixture was stirred for 3 h at ambient temperature. The reaction mixturewas quenched with 2 N HCl solution and then stirred for 4 h at ambienttemperature. The mixture was extracted with EtOAc. The combined EtOAclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. Purification by flash columnchromatography (20-30% EtOAc in hexane) afforded the title compound as aliquid (1.3 g, 20%): ¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 7.89 (s,1H), 5.09 (s1H), 4.23 (m, 2H), 2.27 (br s, 2H), 1.26 (m, 3H); ESIMS m/z293.05 ([M+H]⁺); IR (thin film) 3381, 3306, 1742, 759, 523 cm⁻¹.

Example 54 Preparation of (5-bromo-3-chloropyridin-2-yl)methanaminehydrochloride (CI61)

A stirred solution of ethyl2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (0.5 g, 1.7 mmol) in 3 NHCl (25 mL) was heated at reflux for 4 h. The reaction mixture waswashed with diethyl ether and H₂O. The combined ether layer wasconcentrated under reduced pressure to afford the title compound as anoff-white solid (400 mg, 65%): ¹H NMR (400 MHz, CDCl₃) δ 8.78 (s, 1H),8.70 (br s, 2H), 8.45 (s, 1H), 4.56 (m, 2H); ESIMS m/z 221.15 ([M+H]⁺).

Example 55 Preparation of2-((5-bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (CI62)

To a stirred solution of (5-bromo-3-chloropyridin-2-yl)methanaminehydrochloride (0.3 g, 1.4 mmol) in toluene (40 mL) was added Et₃N (0.41g, 4.08 mmol) and phthalic anhydride (0.24 g, 1.63 mmol), and thereaction mixture was heated at reflux for 2 h. The reaction mixture wasconcentrated under reduced pressure, and the residue was diluted withH₂O and extracted with EtOAc. The combined EtOAc layer was washed withbrine, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The residue was purified by column chromatography (20-30%EtOAc in hexane) to afford the title compound as a white solid (0.25 g,65%): ¹H NMR (400 MHz, CDCl₃) δ 8.78 (s, 1H), 8.45 (s, 1H), 7.88 (m,2H), 7.74 (m, 2H), 4.56 (m, 2H); ESIMS m/z 349 ([m−H]⁻); IR (thin film)3307, 1665, 1114, 813 cm⁻¹.

Example 56 Preparation of2-((3-chloro-5-vinylpyridin-2-yl)methyl)isoindoline-1,3-dione (CI63)

To a stirred solution of2-((5-bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (0.23 g,0.65 mmol) in toluene (10 mL) were added Pd(PPh₃)₄ (3.7 mg, 0.003 mmol),K₂CO₃ (0.269 g, 1.95 mmol) and vinyl boronic anhydride pyridine complex(0.78 g, 3.28 mmol), and the reaction mixture was heated at reflux for16 h. The reaction mixture was filtered, and the filtrate was washedwith H₂O and brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. Purification by flash column chromatography (20-30%EtOAc in hexane) afforded the title compound as an off-white solid (0.2g, 65%): ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1H), 7.91 (m, 2H), 7.77 (m,3H), 7.72 (m, 1H), 6.63 (m, 1H), 5.79 (d, J=16.0 Hz, 1H), 5.39 (d,J=16.0 Hz, 1H), 5.12 (s, 2H); ESIMS m/z 299.20 ([M+H]⁺).

Example 57 Preparation of(E)-2-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichloro-phenyl)but-1-en-1-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione(CI64)

To a stirred solution of2-((3-chloro-5-vinylpyridin-2-yl)methyl)isoindoline-1,3-dione (0.35 g,1.17 mmol) in 1,2-dichlorobenzene (10 mL) were added5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.8 g, 2.3mmol), CuCl (23 mg, 0.12 mmol), 2,2-bipyridyl (0.073 g, 0.234 mmol), andthe reaction mixture was heated at 180° C. for 16 h. The reactionmixture was concentrated under reduced pressure and purified by columnchromatography (20-30% EtOAc in hexane) to afford the title compound asa liquid (0.4 g, 50%): mp 79-82° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.27 (s,1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.36 (s, 2H), 6.51 (d, J=15.6 Hz, 1H),6.32 (dd, J=15.6, 8.0 Hz, 1H), 5.30 (s, 2H), 4.13 (m, 1H); ESIMS m/z 559([M+H]⁺).

Example 58 Preparation of(E)-(3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methanamine(CI65)

To a stirred solution of(E)-2-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione(200 mg, 0.358 mmol) in EtOH (5 mL) was added hydrazine hydrate (89.6mg, 1.79 mmol), and the reaction mixture was heated at reflux for 2 h.The reaction mixture was concentrated under reduced pressure, and theresidue was dissolved in CH₂Cl₂. The organic layer was washed with H₂Oand brine, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure to afford the title compound as a solid (100 mg). The productobtained in this reaction was carried on to the next step withoutfurther purification.

Example 59 Preparation of 4-(bromomethyl)-1-naphthonitrile (CI66)

To a stirred solution of 4-methyl-1-naphthonitrile (5 g, 30 mmol) inCCl₄ (50 mL) under argon atmosphere was added NBS (6.06 g, 34.09 mmol),and the reaction mixture was degassed for 30 min AIBN (0.3 g, 2.1 mmol)was added, and the resultant reaction mixture was heated at reflux for 4h. The reaction mixture was cooled to ambient temperature, diluted withH₂O and extracted with CH₂Cl₂ (3×100 mL). The combined CH₂Cl₂ layer waswashed with brine, dried over Na₂SO₄, and concentrated under reducedpressure. The residue was purified by flash column chromatography (SiO₂,100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as awhite solid (3.8 g, 52%): mp 131-133° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.33(m, 1H), 8.24 (m, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.78 (m, 2H), 7.62 (d,J=8.0 Hz, 1H), 4.95 (s, 2H); ESIMS m/z 245.92 ([M+H]⁺); IR (thin film)2217 cm⁻¹.

Example 60 Preparation of 4-(bromomethyl)-1-naphthaldehyde (CI67)

To a stirred solution of 4-(bromomethyl)-1-naphthonitrile (8 g, 33 mmol)in toluene (100 mL) at 0° C. was added dropwise DIBAL-H (1.0 M solutionin toluene; 43 mL), and the reaction mixture was stirred at 0° C. for 1h. 3 N HCl in H₂O (50 mL) was added to the mixture until it became awhite slurry and then additional 1 N HCl (20 mL) was added. The organiclayer was collected and the aqueous layer was extracted with EtOAc(3×100 mL). The combined organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. Purification by flash columnchromatography (SiO₂, 100-200 mesh; 5% EtOAc in petroleum ether)afforded the title compound as a white solid (7 g, 88%): mp 115-116° C.;¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 9.35 (m, 1H), 8.22 (m, 1H),7.90 (d, J=8.0 Hz, 1H), 7.75 (m, 3H), 4.95 (s, 2H); ESIMS m/z 248.88([M+H]⁺).

Example 61 Preparation of4-((1,3-dioxoisoindolin-2-yl)methyl)-1-naphthaldehyde (CI68)

To a stirred solution of 4-(bromomethyl)-1-naphthaldehyde (7 g, 28 mmol)in DMF (100 mL) was added potassium phthalimide (7.3 g, 39.5 mmol), andthe mixture was heated at 85° C. for 2 h. The reaction mixture wascooled to ambient temperature and diluted with H₂O (100 mL). Theobtained solid was separated by filtration and dried under vacuum toafford the title compound as a white solid (8.8 g, 98%): mp 190-192° C.;¹H NMR (400 MHz, CDCl₃) δ 10.39 (s, 1H), 9.25 (m, 1H), 8.41 (m, 1H),8.10 (d, J=8.0 Hz, 1H), 7.95 (m, 4H), 7.80 (m, 4H), 7.61 (m, 4H), 5.39(s, 2H); ESIMS m/z 316.09 ([M+H]⁺); IR (thin film) 1708 cm⁻¹.

Example 62 Preparation of 2-((4-vinylnaphthalen-1-yl)methyl)isoindoline-1,3-dione (CI69)

To a stirred solution of4-((1,3-dioxoisoindolin-2-yl)methyl)-1-naphthaldehyde (9 g, 28.5 mmol)in 1,4-dioxane (100 mL) were added K₂CO₃ (6 g, 42.8 mmol) and methyltriphenyl phosphonium bromide (15.3 g, 35.7 mmol) at ambienttemperature. The reaction mixture was heated at 100° C. for 14 h andthen was cooled to ambient temperature. The reaction mixture wasfiltered, and the obtained filtrate was concentrated under reducedpressure. Purification by flash chromatography (SiO₂, 100-200 mesh; 20%EtOAc in petroleum ether) afforded the title compound as a white solid(6 g, 67%): mp 146-147° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.35 (m, 2H), 7.95(m, 4H), 7.65 (m, 4H), 7.39 (m, 1H), 5.81 (m, 1H), 5.45 (m, 1H), 5.21(s, 2H); ESIMS m/z 314.13 ([M+H]⁺).

Example 63 Preparation of(E)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)isoindoline-1,3-dione(CI70)

To a stirred solution of2-((4-vinylnaphthalen-1-yl)methyl)isoindoline-1,3-dione (1.5 g, 4.79mmol) in 1,2-dichlorobenzene (15 mL) were added1-(1-bromo-2,2,2-trifluoroethyl)-3,4,5-trichlorobenzene (3.2 g, 9.5mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (0.149 g, 0.95 mmol),and the resultant reaction mixture was degassed with argon for 30 minand then stirred at 180° C. for 14 h. After the reaction was deemedcomplete by TLC, the reaction mixture was cooled to ambient temperatureand filtered, and the filtrate was concentrated under reduced pressure.Purification by flash chromatography (SiO₂, 100-200 mesh; 25-30% EtOAcin petroleum ether) afforded the title compound as an off-white solid(1.5 g, 56%): mp 158-160° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.40 (m, 1H),7.89 (m, 2H), 7.74 (m, 2H), 7.64 (m, 2H), 7.58 (m, 2H), 7.46 (s, 2H),7.36 (m, 2H), 6.31 (m, 1H), 5.30 (s, 2H), 4.21 (m, 1H); ESIMS m/z 572.08([M−H]⁻).

Example 64 Preparation of(E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine(CI71)

To a stirred solution of(E)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)isoindoline-1,3-dione(0.4 g, 0.7 mmol) in EtOH was added hydrazine hydrate (0.18 g, 3.5mmol), and the resultant reaction mixture was heated at 80° C. for 2 h.The reaction mixture was filtered, and the filtrate was concentrated.The residue was dissolved in CH₂Cl₂, and the solution was washed withbrine, dried over Na₂SO₄, and concentrated under reduced pressure. Thetitle compound was isolated as a gummy liquid (150 mg, 50%). The productobtained in this reaction was carried on to the next step withoutfurther purification.

Example 65 Preparation of 2-((4-bromophenyl)amino)isoindoline-1,3-dione(CI72)

To a stirred solution of (4-bromophenyl)hydrazine hydrochloride (0.5 g,2.2 mmol) in glacial acetic acid (8 mL) was added phthalic anhydride(0.398 g, 2.690 mmol), and the reaction mixture was stirred at 130° C.for 1 h under a nitrogen atmosphere. The reaction mixture was quenchedwith satd aq. NaHCO₃ solution and filtered to give a solid. Purificationby column chromatography (SiO₂, 0-10% EtOAc in petroleum ether) affordedthe title compound as a solid (60 mg, 84%): mp 205-206° C.; ¹H NMR (400MHz, CDCl₃) δ 8.71 (s, 1H), 7.99 (m, 4H), 7.32 (d, J=8.8 Hz, 2H), 6.79(d, J=8.8 Hz, 2H); ESIMS m/z 314.95 ([M−H]⁻).

Example 66 Preparation of 2-((4-vinylphenyl)amino)isoindoline-1,3-dione(CI73)

To a solution of 2-(4-bromophenylamino)isoindoline-1,3-dione (2 g, 6mmol) in 1,2-dimethoxyethane (20 mL) and H₂O (4 mL) were added vinylboronic anhydride pyridine complex (4.57 g, 18.98 mmol) and K₂CO₃ (1.3g, 9.5 mmol) followed by Pd(PPh₃)₄ (0.219 g, 0.189 mmol). The resultantreaction mixture was heated at 150° C. in a microwave for 30 min andthen was concentrated under reduced pressure. Purification by columnchromatography (SiO₂, 15% EtOAc in petroleum ether) afforded the titlecompound as a solid (200 mg, 13%): mp 174-176° C.; ¹H NMR (400 MHz,CDCl₃) δ 8.65 (s, 1H), 7.94 (m, 4H), 7.29 (d, J=8.4 Hz, 2H), 6.72 (d,J=8.4 Hz, 2H), 6.61 (m, 1H), 5.61 (d, J=17.6 Hz, 1H), 5.05 (d, J=11.2Hz, 1H); ESIMS m/z 263.18 ([M−H]⁻).

Example 67 Preparation of(E)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)amino)isoindoline-1,3-dione(CI74)

To a stirred solution of 2-(4-vinylphenylamino)isoindoline-1,3-dione(0.3 g, 1.1 mmol) in 1,2-dichlorobenzene (5 mL) were added CuCl (0.022g, 0.273 mmol), 2,2-bipyridyl (0.07 g, 0.46 mmol) and5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.77 g, 2.27mmol). The reaction mixture was degassed with argon for 30 min and washeated at 180° C. for 2 h. The reaction mixture was then concentratedunder reduced pressure, and the residue was purified by columnchromatography (SiO₂, 0-30% EtOAc in petroleum ether) to afford thetitle compound as a solid (450 mg, 75%): mp 187-189° C.; ¹H NMR (400MHz, CDCl₃) δ 8.75 (s, 1H), 7.96 (m, 4H), 7.82 (s, 2H), 7.37 (d, J=8.8Hz, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.61 (m, 2H), 6.58 (m, 1H), 4.59 (m,1H); ESIMS m/z 523.05 ([M−H]⁻).

Example 68 Preparation of(E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydrazine(CI75)

To a stirred solution of(E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)phenylamino)isoindoline-1,3-dione(0.16 g, 0.31 mmol) in EtOH (5 mL), was added hydrazine hydrate (0.076g, 1.52 mmol), and the reaction mixture was heated at 85° C. for 1 h.The reaction mixture was cooled to ambient temperature and filtered, andthe filtrate was concentrated under reduced pressure to afford the titlecompound as a solid (0.08 g, 66%) which was carried on to the next stepwithout further purification.

Example 69 Preparation of 2-(4-vinylphenoxy)isoindoline-1,3-dione (CI76)

To a stirred solution of 4-vinylphenylboronic acid (2 g, 13 mmol),2-hydroxyisoindoline-1,3-dione (3.63 g, 24.53 mmol), and CuCl (1.214 g12.26 mmol) in 1,2-dichloroethane (50 mL) was added pyridine (1.065 g,13.48 mmol), and the resultant reaction mixture was stirred at ambienttemperature for 48 h. The reaction mixture was diluted with H₂O andextracted with CHCl₃. The combined CHCl₃ layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure. Purificationby flash column chromatography (SiO₂; 20% EtOAc in petroleum ether)afforded the title compound as a white solid (2 g, 63%): mp 129-131° C.;¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, J=2.0 Hz, 2H), 7.82 (d, J=3.2 Hz,2H), 7.38 (d, J=2.0 Hz, 2H), 7.14 (d, J=2.0 Hz, 2H), 6.70 (m, 1H), 5.83(d, J=16.0 Hz, 1H), 5.22 (d, J=10.8 Hz, 1H); ESIMS m/z 266.12 ([M+H]⁺).

Example 70 Preparation of(E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenoxy)isoindoline-1,3-dione(CI77)

To a stirred solution of 2-(4-vinylphenoxy)isoindoline-1,3-dione (0.3 g,1.1 mmol) in 1,2-dichlorobenzene (10 mL) was added1-(1-bromoethyl)-3,4,5-trichlorobenzene (769 mg, 2.26 mmol), CuCl (22mg, 0.22 mmol) and 2,2-bipyridyl (35 mg, 0.44 mmol), and the resultantreaction mixture was degassed with argon for 30 min and heated to 180°C. for 24 h. The reaction mixture was cooled to ambient temperature andfiltered, and the filtrate was concentrated under reduced pressure. Thecrude material was purified by column chromatography (SiO₂, 100-200mesh; 20% EtOAc in petroleum ether) to afford the title compound as asolid (0.29 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 7.90 (m, 1H), 7.62 (m,2H), 7.50 (m, 1H), 7.40 (s, 2H), 7.12 (s, 1H), 6.90 (m, 2H), 6.60 (m,2H), 6.20 (m, 1H), 4.08 (m, 1H); ESIMS m/z 524.09 ([M−H]⁻).

Example 71 Preparation of(E)-O-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydroxylamine(CI78)

To a stirred solution of(E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)phenoxy)isoindoline-1,3-dione(0.2 g, 0.4 mmol) in EtOH was added hydrazine hydrate (0.1 g, 1.9 mmol),and the resultant reaction mixture was heated at 90° C. for 1 h. Thereaction mixture was filtered, and the filtrate was concentrated. Theresidue was dissolved in CH₂Cl₂. washed with brine, dried over Na₂SO₄and concentrated under reduced pressure to afford the crude titlecompound as a gummy liquid (0.08 g, 53%): ¹H NMR (400 MHz, CDCl₃) δ 7.40(s, 2H), 6.98 (s, 1H), 6.82 (s, 2H), 6.48 (m, 1H), 6.20 (m, 1H), 5.02(s, 1H), 4.08 (m, 1H); ESIMS m/z 394.94 ([M−H]⁻).

Example 72 Preparation of(E)-N-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)benzyl)acetamide(CC1)

To a stirred solution of(E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine(0.3 g, 0.8 mmol) in DCM (10 mL) was added acetic anhydride (0.12 mL,1.14 mmol), and TEA (0.217 mL, 1.52 mmol), and the resultant reactionmixture was stirred at ambient temperature for 6 h. The reaction mixturewas diluted with H₂O and extracted with DCM. The combined DCM layer waswashed with brine, dried over Na₂SO₄, and concentrated under reducedpressure. Purification by flash column chromatography (SiO₂, 100-200mesh; 30-50% ethyl acetate in hexane) afforded the title compound as aoff-white solid (0.2 g, 60%) mp 107-109° C.; ¹H NMR (400 MHz, CDCl₃) δ7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0,8.0 Hz, 1H), 5.75 (br s, 1H), 4.46 (d, J=6 Hz, 2H), 4.01 (m, 1H), 2.11(s, 3H); ESIMS m/z 402.00 ([M+H]⁺). Compounds CC2-CC6 in Table 1 weremade in accordance with the procedures disclosed in Example 72. Inaddition, compound DC56 in Table 1 was made from compound DC55 inaccordance with the procedures disclosed in Example 72.

Example 73 Preparation of(E)-N-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)acetamide(CC7)

To a stirred solution of(E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine(0.3 g, 0.8 mmol) in DMF (5 mL) was added 2,2,2-trifluoropropanoic acid(97 mg, 0.76 mmol), HOBt.H₂O (174 mg, 1.14 mmol) and EDC.HCl (217 mg,1.14 mmol) and DIEA (196 mg, 1.52 mmol), and the resultant reactionmixture was stirred at ambient temperature for 18 h. The reactionmixture was diluted with H₂O and extracted with EtOAc. The combinedEtOAc layer was washed with brine, dried over Na₂SO₄, and concentratedunder reduced pressure. Purification by flash column chromatography(SiO₂, 100-200 mesh; ethyl acetate in hexane (30-50% afforded the titlecompound as a off-white solid (0.2 g, 60%): mp 127-128° C.; ¹H NMR (400MHz, CDCl₃) δ 7.42 (m, 4H), 7.24 (m, 2H), 6.53 (d, J=16.0 Hz, 1H), 6.36(dd, J=16.0, 8.0 Hz, 1H), 5.86 (br s, 1H), 4.51 (d, J=6.0 Hz, 2H), 4.05(m, 1H), 2.02 (s, 3H); ESIMS m/z 436.03 ([M+H]⁺).

Compounds CC8-CC28 in Table 1 were made in accordance with theprocedures disclosed in Example 73.

Example 74 Preparation of(E)-N-(pyridin-2-ylmethyl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)cyclopropanecarboxamide(CC29)

Step 1:(E)-1-(Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)methanamine

(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)phenyl)methanamine(0.46 g, 1 mmol) was dissolved in CH₃OH (3 mL). To this was addedpyridine-2-carbaldehyde (0.107 g, 1 mmol). The reaction mixture wasstirred for 1 h. After 1 h, NaBH₄ (0.076 g, 2 mmol) was added and leftat ambient temperature for 3 h. The reaction mixture was concentrated togive an oily residue. Purification by flash column chromatography (SiO₂,100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as apale yellow liquid (0.22 g, 40%): ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d,J=4.8 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H),7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0Hz, 1H), 4.10 (m, 1H), 4.02 (s, 2H), 3.96 (s, 2H); ESIMS m/z 552.95([M+H]⁺); IR (thin film) 3338, 1114, 808 cm⁻¹.

Step 2:(E)-N-(Pyridin-2-ylmethyl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)cyclopropanecarboxamide

(E)-1-(Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzyl)methanamine(0.27 g, 0.05 mmol) was taken up in CH₂Cl₂ (3 mL). To this was addedEt₃N (0.14 mL, 0.1 mmol). The reaction mixture was stirred for 10 minAfter 10 min, the reaction mixture was cooled to 0° C., andcyclopropylcarbonyl chloride (0.08 mL, 0.075 mmol) was added. Thereaction mixture was stirred at ambient temperature for 1 h and then waswashed with H₂O and satd aq NaHCO₃ solution. The organic layer was driedover anhydrous Na₂SO₄ and evaporated to obtain pale yellow gummymaterial (0.15 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J=4.6 Hz,1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H),7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H),5.02 (s, 1H), 4.8 (s, 1H), 4.8 (d, J=10 Hz, 2H), 4.10 (m, 1H), 1.8 (m,1H), 1.2 (m, 2H), 0.6 (m, 2H); ESIMS m/z 620.86 ([M−H]⁻); IR (thin film)1645, 1115, 808 cm⁻¹.

Example 75 Preparation of(E)-N-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-3-(methylsulfonyl)propanamide(CC30)

(E)-N-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-3-(methylthio)propanamide(0.15 g, 0.28 mmol) was treated with oxone (0.175 g, 0.569 mmol) in 1:1acetone:water (20 mL) for 4 h at ambient temperature. The acetone wasevaporated to obtain a white solid (0.095 g, 60%): mp 101-104° C.; ¹HNMR (400 MHz, CDCl₃) δ 7.41 (m, 4H), 7.24 (m, 1H), 6.53 (d, J=16.0 Hz,1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 6.12 (br s, 1H), 4.53 (m, 2H), 4.10(m, 1H), 3.42 (m, 2H), 2.91 (s, 3H), 2.78 (m, 2H); ESIMS m/z 559.75([M−H]⁻).

Example 76 Preparation of(E)-1-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)-3-ethylurea(CC31)

To a stirred solution of(E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine(0.2 g, 0.5 mmol) in CH₂Cl₂ (5 mL) at 0° C. were added Et₃N (0.141 mL, 1mmol) and ethylisocyanate (0.053 g, 0.75 mmol), and the reaction mixturewas stirred for 1 h at 0° C. The reaction mixture was diluted withCH₂Cl₂. The organic layer was washed with H₂O and brine, dried overNa₂SO₄, and concentrated under reduced pressure. Purification by columnchromatography (SiO₂, 100-200 mesh; 30-50% EtOAc in hexane) afforded thetitle compound as a solid (0.141 g, 60%): mp 177-178° C.; ¹H NMR (400MHz, CDCl₃) δ 7.58 (m, 2H), 7.41 (m, 3H), 7.24 (m, 1H), 6.53 (d, J=16.0Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 4.70 (br s, 1H), 4.43 (s, 2H),4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H); ESIMS m/z 463 ([M−H]⁻).

Compounds CC32-CC35 in Table 1 were made in accordance with theprocedures disclosed in Example 76.

Example 77 Preparation of(E)-3-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-1,1-dimethylurea(CC36)

To a stirred solution of(E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine(0.2 g, 0.5 mmol) in CH₂Cl₂ (5 mL) at 0° C. were added Et₃N (0.141 mL, 1mmol) and N,N-dimethylcarbamoyl chloride (0.08 g, 0.075 mmol), and thereaction mixture was stirred for 1 h at 0° C. The reaction mixture wasdiluted with CH₂Cl₂. The organic layer was washed with H₂O and brine,dried over Na₂SO₄, and concentrated under reduced pressure. Purificationby column chromatography (SiO₂, 100-200 mesh; 30-50% EtOAc in hexane)afforded the title compound as a solid (0.15 g, 60%): ¹H NMR (400 MHz,CDCl₃) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd,J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m,1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([m−H]⁻); IR (thin film)3350, 1705, 1114, 808 cm⁻¹.

Example 78 Preparation of(E)-1-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-3-ethylthiourea(CC37)

To a stirred solution of(E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine(0.2 g, 0.5 mmol) in CH₂Cl₂ (5 mL) at 0° C. were added Et₃N (0.141 mL, 1mmol) and ethyl isothiocyanate (0.053 g, 0.75 mmol), and the reactionmixture was stirred for 1 h at 0° C. The reaction mixture was dilutedwith CH₂Cl₂. The organic layer was washed with H₂O and brine, dried overNa₂SO₄, and concentrated under reduced pressure. Purification by columnchromatography (SiO₂, 100-200 mesh; 30-50% EtOAc in hexane) afforded thetitle compound as a solid (0.14 g, 60%): mp 88-91° C.; ¹H NMR (400 MHz,CDCl₃) δ 7.49 (d, J=8 Hz, 1H), 7.41 (d, J=7.2 Hz, 2H), 7.26 (m, 2H),6.50 (d, J=16 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 6.0 (br s, 1H),5.73 (br s, 1H), 4.80 (br s, 2H), 4.09 (m, 1H), 1.23 (m, 3H); ESIMS m/z515.01 ([M+H]⁺).

Compound CC38 in Table 1 was made in accordance with the proceduresdisclosed in Example 78.

Example 79 Preparation of(E)-tert-butyl(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)-3-ethylurea(CC39)

To a stirred solution of(E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine(0.2 g, 0.5 mmol in CH₂Cl₂ (5 mL) at 0° C. were added Et₃N (0.141 mL, 1mmol) and di-tert-butyl dicarbonate (0.163 mL, 0.75 mmol), and thereaction mixture was stirred for 4 h at ambient temperature. Thereaction mixture was diluted with CH₂Cl₂. The organic layer was washedwith H₂O and brine, dried over Na₂SO₄, and concentrated under reducedpressure. Purification by column chromatography (SiO₂, 100-200 mesh;10-20% EtOAc in hexane) afforded the title compound as a white solid(0.147 g, 60%): ¹H NMR (400 MHz, CDCl₃) δ 7.39 (m, 4H), 7.28 (m, 1H),6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H),4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 1.53 (s, 9H); ESIMS m/z 526.09([m−H]⁻); IR (thin film) 3350, 1705, 1114, 808 cm⁻¹.

Compound CC40 in Table 1 was made in accordance with the proceduresdisclosed in Example 79.

Example 80 Preparation of (E)-methyl2-((2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)amino)-2-oxoacetate(CC41)

To a stirred solution of(E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine(0.2 g, 0.5 mmol) in CH₂Cl₂ (5 mL) at 0° C. were added Et₃N (0.141 mL, 1mmol) and methyl 2-chloro-2-oxoacetate (0.09 g, 0.75 mmol), and thereaction mixture was stirred for 1 h at 0° C. The reaction mixture wasdiluted with CH₂Cl₂. The organic layer was washed with H₂O and brine,dried over Na₂SO₄, and concentrated under reduced pressure. Purificationby column chromatography (SiO₂, 100-200 mesh; 20% EtOAc in hexane)afforded the title compound as a solid (0.12 g, 50%): ¹H NMR (400 MHz,CDCl₃) δ 7.48 (m, 1H). 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55(d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.60 (d, J=4.4 Hz,2H), 4.18 (m, 1H), 3.85 (s, 3H); ESIMS m/z 512.22 ([m−H]⁻); IR (thinfilm) 1740, 1701, 1114, 808 cm⁻¹.

Example 81 Preparation of(E)-N¹-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-N²-(2,2,2-trifluoroethyl)oxalamide(CC42)

To a stirred solution of 2,2,2-trifluoroethylamine hydrochloride (0.1 g,0.77 mmol) in CH₂Cl₂ (10 mL) was added dropwise trimethylaluminum (2 Msolution in toluene; 0.39 mL, 0.77 mmol), and the reaction mixture wasstirred at 25° C. for 30 min A solution of (E)-methyl2-((2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-2-oxoacetate(0.2 g, 0.38 mmol) in CH₂Cl₂ (5 mL) was added dropwise to the reactionmixture at 25° C. The reaction mixture was stirred at reflux for 18 h,cooled to 25° C., quenched with 0.5 N HCl solution (50 mL) and extractedwith EtOAc (2×50 mL). The combined organic extracts were washed withbrine, dried over Na₂SO₄, and concentrated under reduced pressure. Thecrude compound was purified by flash chromatography (SiO₂, 100-200 mesh;20%-40% EtOAc in n-hexane) to afford the title compound (0.13 g, 60%):mp 161-163° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (br s, 2H), 7.90 (s,2H), 7.75 (s, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 6.93 (m, 1H), 6.75 (m,1H), 4.80 (m, 1H), 4.40 (s, 2H), 3.90 (s, 2H); ESIMS m/z 578.96([M−H]⁻).

Example 82 Preparation of(E)-N-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)pyridin-2-amine(CC43)

To a stirred solution of N-(2-chloro-4-vinylbenzyl)pyridin-2-amine (0.3g, 1.22 mmol) in 1,2-dichlorobenzene (5 mL) were added5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.83 g, 2.44mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (76 mg, 0.48 mmol). Theresultant reaction mixture was degassed with argon for 30 min and thenstirred at 180° C. for 24 h. After the reaction was deemed complete byTLC, the reaction mixture was cooled to ambient temperature andfiltered, and the filtrate was concentrated under reduced pressure.Purification by flash chromatography (SiO₂, 100-200 mesh; 15% EtOAc inn-hexane) afforded the title compound as an off-white solid (0.2 g,35%): mp 140-142° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J=4.0 Hz, 1H),7.40 (m, 5H), 7.22 (m, 1H), 6.61 (m, 2H), 6.35 (m, 2H), 4.94 (br s, 1H),4.61 (d, J=6.4 Hz, 2H), 4.11 (m, 1H); ESIMS m/z 505.39 ([M+H]⁺).

Example 83 Preparation of(E)-N-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-but-1-en-1-yl)pyridin-2-yl)methyl)-3,3,3-trifluoropropanamide(CC44)

To a stirred solution of(E)-(3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methanamine(0.1 g, 0.2 mmol) in CH₂Cl₂ (5 mL) were added 3,3,3-trifluoropropanoicacid (45 mg, 0.350 mmol), EDC.HCl (67 mg, 0.350 mmol), HOBt.H₂O (71 mg,0.467 mmol) and DIEA (60.2 mg, 0.467 mmol), and the reaction mixture wasstirred at ambient temperature for 18 h. The reaction mixture wasdiluted with CH₂Cl₂ and washed with H₂O. The combined CH₂Cl₂ layer waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. Purification by flash column chromatography (SiO₂,100-200 mesh; 15% EtOAc in petroleum ether) afforded the title compoundas a pale yellow liquid (30 mg, 35%): ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s,1H), 7.77 (s, 1H), 7.47 (br s, 1H), 7.40 (s, 2H), 6.58 (d, J=16.0 Hz,1H), 6.45 (dd, J=16.0, 8.0 Hz, 1H), 4.68 (d, J=4.0 Hz, 2H), 4.14 (m,1H), 3.24 (q, J=10.8 Hz, 2H); ESIMS m/z 536.88 ([M−H]⁻); IR (thin film)3320, 1674, 1114, 808.

Compound CC45 in Table 1 was made in accordance with the proceduresdisclosed in Example 83.

Example 84 Preparation of(E)-3,3,3-trifluoro-N-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)propanamide(CC46)

To a stirred solution of(E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine(0.1 g, 0.22 mmol) in CH₂Cl₂ (8 mL) were added 3,3,3-trifluoropropanoicacid (0.032 g, 0.24 mmol), HOBt.H₂O (52 mg, 0.33 mmol), EDC.HCl (0.065g, 0.33 mmol) and DIEA (0.044 g, 0.45 mmol), and the resultant reactionmixture was stirred at ambient temperature for 18 h. The reactionmixture was diluted with H₂O and extracted with EtOAc (3×30 mL). Thecombined EtOAc layer was washed with brine, dried over Na₂SO₄, andconcentrated under reduced pressure. Purification by flash columnchromatography (SiO₂, 100-200 mesh; 15% EtOAc in n-hexane) afforded thetitle compound as a gummy material (60 mg, 50%): mp 151-153° C.; ¹H NMR(400 MHz, CDCl₃) δ 8.06 (m, 1H), 7.61 (m, 4H), 7.48 (s, 2H), 7.44 (d,J=8.0 Hz, 1H), 7.38 (m, 1H), 6.42 (m, 1H), 5.92 (br s, 1H), 4.92 (m,2H), 4.24 (m, 1H), 3.12 (m, 2H); ESIMS m/z 554.04 ([M−H]⁻).

Compounds CC47-CC48 in Table 1 were made in accordance with theprocedures disclosed in Example 84.

Example 85 Preparation of(E)-1-ethyl-3-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)urea(CC49)

To a stirred solution of(E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine(0.1 g, 0.22 mmol) in CH₂Cl₂ at 0° C. were added Et₃N (0.064 mL, 0.44mmol) and ethylisocyanate (0.023 mL, 0.33 mmol), and the reactionmixture was stirred for 1 h at 0° C. The reaction mixture was dilutedwith CH₂Cl₂. The organic layer was washed with H₂O and brine, dried overNa₂SO₄, and concentrated under reduced pressure. Purification by columnchromatography (SiO₂, 100-200 mesh; 30% EtOAc in hexane) afforded thetitle compound as a solid (0.07 g, 60%): mp 84-87° C.; ¹H NMR (400 MHz,CDCl₃) δ 8.06 (m, 1H), 7.98 (m, 1H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44(d, J=8.0 Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H), 4.6 (br s,1H), 4.24 (m, 1H), 3.21 (m, 2H), 1.2 (t, J=4.6 Hz, 3H); ESIMS m/z 515.33([M+H]⁺).

Example 86 Preparation of(E)-N′-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)cyclopropanecarbohydrazide(CC50)

To a stirred solution of(E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydrazine(0.1 g, 0. 3 mmol) in CH₂Cl₂ (10 mL) was added DIEA (65 mg, 0.51 mmol),HOBt.H₂O (59 mg, 0.38 mmol), EDC.HCl (73 mg, 0.38 mmol) andcyclopropanecarbonyl chloride (0.024 g, 0.28 mmol), and the reactionmixture was stirred at ambient temperature for 1 h. The reaction mixturewas diluted with satd aq NaHCO₃ solution and extracted with CH₂Cl₂. Thecombined CH₂Cl₂ layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. Purification by flashcolumn chromatography (SiO₂; 5-25% EtOAc in petroleum ether) affordedthe title compound as a solid (65 mg, 55%): mp 138-140° C.; ¹H NMR (400MHz, CDCl₃) δ 9.81 (s, 1H), 7.90 (s, 1H), 7.84 (s, 2H), 7.34 (d, J=8.4Hz, 2H), 6.65 (d, J=15.6 Hz, 1H), 6.61 (m, 1H), 6.57 (s, 1H), 6.48 (dd,J=15.6, 8.8 Hz, 1H), 4.74 (m, 1H), 1.64 (m, 1H), 0.75 (m, 4H); ESIMS m/z461.32 ([M−H]⁻).

Compound CC51 in Table 1 was made in accordance with the proceduresdisclosed in Example 86.

Example 87 Preparation of(E)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenoxy)cyclopropanecarboxamide(CC52)

To a stirred solution of(E)-O-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydroxylamine(0.15 g, 0.38 mmol) in CH₂Cl₂ (5 mL) was added EDC.HCl (0.109 g, 0.569mmol), HOBt.H₂O (0.087 g, 0.569 mmol), DIEA (0.097 g, 0.758 mmol) andcyclopropanecarboxylic acid (0.049 g, 0.569 mmol). The resultantreaction mixture was stirred at ambient temperature for 18 h. Thereaction mixture was diluted with H₂O and extracted with CHCl₃ (35 mL)The combined CHCl₃ layer was washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. Purification by flash columnchromatography (SiO₂; 20% EtOAc in hexane) afforded the title compoundas a brown liquid (0.06 g, 34%): ¹H NMR (400 MHz, CDCl₃) δ 7.40 (s, 2H),7.18 (s, 1H), 7.08 (s, 1H), 6.85 (m, 1H), 6.45 (m, 1H), 6.65 (m, 1H),6.20 (m, 1H), 5.55 (s, 1H), 4.08 (m, 1H), 1.90 (m, 1H), 1.30-1.10 (m,4H); ESIMS m/z 464.87 ([M−H]⁻).

Compound CC53 in Table 1 was made in accordance with the proceduresdisclosed in Example 87.

Example 88 Preparation of(Z)-3,3,3-trifluoro-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)propanamide(CC54)

A silicon borate vial was charged with(E)-3,3,3-trifluoro-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)propanamide(133 mg, 0.269 mmol) and dimethyl sulfoxide (DMSO; 10 mL). The mixturewas placed within 0.6 to 1 meter (m) of a bank of eight 115 wattSylvania FR48T12/350BL/VHO/180 Fluorescent Tube Black Lights and four115 watt Sylvania (daylight) F48T12/D/VHO Straight T12 Fluorescent TubeLights for 72 h. The mixture was concentrated in vacuo and purified byreverse phase chromatography to give the title compound as a colorlessoil (11 mg, 8%): ¹H NMR (300 MHz, CDCl₃) δ 7.28 (s, 2H), 7.25 (m, 2H),7.10 (d, J=8.0 Hz, 2H), 6.89 (d, J=11.4 Hz, 1H), 6.07 (br s, 1H), 6.01(m, 1H), 4.51 (d, J=5.8 Hz, 2H), 4.34 (m, 1H), 3.12 (q, J=7.5 Hz, 2H);¹³C NMR (101 MHz, CDCl₃) δ 162.44, 137.20, 135.38, 135.23, 134.82,134.68, 131.71, 129.00, 128.80, 128.69, 128.10, 127.96, 122.63, 76.70,47.33 (q, J=28 Hz), 43.59, 42.12 (q, J=30 Hz); ESIMS m/z 504 ([M+H]⁺).

Compounds DC46, AC93. AC94 in Table 1 were made in accordance with theprocedures disclosed in Example 88.

Example 89 Preparation of1-(1-bromo-2,2,2-trifluoroethyl)-3-chlorobenzene (DI2)

The title compound was synthesized in two steps via1-(3-chlorophenyl)-2,2,2-trifluoroethanol (DI1, prepared as in Step 1,Method B in Example 1); isolated as a colorless viscous oil (1.5 g,75%): ¹H NMR (400 MHz, CDCl₃) δ 7.50 (s, 1H), 7.42-7.35 (m, 3H), 5.02(m, 1H), 2.65 (br s, 1H)) and Step 2 in Example 1 and isolated (0.14 g,22%): ¹H NMR (400 MHz, CDCl₃) δ 7.50 (br s, 1H), 7.42-7.35 (m, 3H), 5.07(m, 1H).

The following compounds were made in accordance with the proceduresdisclosed in Example 89.

(1-Bromo-2,2,2-trifluoroethyl)benzene (DI4)

2,2,2-Trifluoro-1-phenylethanol (DI3) was isolated (10 g, 80%): ¹H NMR(300 MHz, CDCl₃) δ 7.48 (m, 2H), 7.40 (m, 3H), 5.02 (m, 1H), 2.65 (d,J=7.1 Hz, 1H). The title compound (DI4) was isolated as a liquid (8.0 g,60%): ¹H NMR (400 MHz, CDCl₃) δ 7.50 (m, 2H), 7.40 (m, 3H), 5.00 (q,J=7.5 Hz, 1H).

1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dimethylbenzene (DI20)

1-(3,5-Dimethylphenyl)-2,2,2-trifluoroethanol (DI19) was isolated an offwhite solid: ¹H NMR (400 MHz, CDCl₃) δ 7.05 (s, 2H), 7.02 (s, 1H), 4.95(m, 1H), 2.32 (s, 6H); ESIMS m/z 204 GMT). The title compound (DI20) wasisolated (3.0 g, 51%).

1-(1-Bromo-2,2,2-trifluoroethyl)-2,4-dichlorobenzene (DI22)

1-(2,4-Dichlorophenyl)-2,2,2-trifluoroethanol (DI21) was isolated as anoff white powder (5.3 g, 61%): mp 49-51° C.; ¹H NMR (400 MHz, CDCl₃) δ7.62-7.66 (d, 1H), 7.42-7.44 (d, 1H), 7.32-7.36 (d, 1H), 5.6 (m, 1H),2.7 (s, 1H); ESIMS m/z 244 ([M]⁺). The title compound (DI22) wasisolated (3.2 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.72 (m, 1H),7.4-7.42 (m, 1H), 7.3-7.38 (m, 1H), 5.7-5.8 (m, 1H).

1-(1-Bromo-2,2,2-trifluoroethyl)-2,3-dichlorobenzene (DI24)

1-(2,3-Dichlorophenyl)-2,2,2-trifluoroethanol (DI23) was isolated as apale yellow oil (5.2 g, 60%): ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.64 (d,1H), 7.52-7.54 (m, 1H), 7.29-7.33 (t, 1H), 5.6-5.76 (m, 1H), 2.7 (s,1H); ESIMS m/z 243.9 ([M]⁺). The title compound (DI24) was isolated asan oil (8.7 g, 60%): ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.71 (m, 1H),7.44-7.52 (m, 1H), 7.27-7.3 (s, 1H), 5.81-5.91 (m, 1H).

2-(1-Bromo-2,2,2-trifluoroethyl)-1,4-dichlorobenzene (DI26)

1-(2,5-Dichlorophenyl)-2,2,2-trifluoroethanol (DI25) was isolated as ayellow oil (4.1 g, 60%): ¹H NMR (400 MHz, CDCl₃) δ 7.68-7.7 (s, 1H),7.3-7.37 (m, 2H), 5.51-5.6 (m, 1H), 2.7 (s, 1H); ESIMS m/z 244 ([M]⁺)).The title compound (DI26) was isolated (3.0 g, 60%): ¹H NMR (400 MHz,CDCl₃) δ 7.7-7.78 (m, 1H), 7.3-7.4 (m, 2H), 5.7-5.8 (m, 1H).

1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-bis(trifluoromethyl)benzene (DI28)

1-(3,5-Bis(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (DI27) wasisolated (3.8 g, 60%): ¹H NMR (400 MHz, CDCl₃) δ 7.98 (m, 3H), 5.25 (m,1H), 3.2 (br, 1H); ESIMS m/z 312.2 ([M]⁺). The title compound (DI28) wasprepared and carried on crude.

1-(1-Bromo-2,2,2-trifluoroethyl)-2,3,5-trichlorobenzene (DI30)

2,2,2-Trifluoro-1-(2,3,5-trichlorophenyl)ethanol (DI29) was isolated asa white solid (4.0 g, 60%): mp 113-115° C.; ¹H NMR (400 MHz, CDCl₃) δ7.62 (d, 1H), 7.50 (d, 1H), 5.60-5.70 (m, 1H), 2.75 (s, 1H); ESIMS m/z278.0 ([M⁺]). The title compound (DI30) was isolated (2.9 g, 60%): ¹HNMR (400 MHz, CDCl₃) δ 7.70 (d, 1H), 7.50 (d, 1H), 5.72-5.82 (m, 1H).

1-(1-Bromo-2,2,2-trifluoroethyl)-3-chloro-5-(trifluoromethyl)benzene(DI32)

1-(3-Chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (DI31) wasisolated as a pale yellow oil (2.0 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ7.51 (m, 3H), 5.08 (m, 1H), 2.81 (s, 1H); ESIMS m/z 278.1 ([M]⁺). Thetitle compound (DI32) was isolated oil (2.0 g, 40%): ESIMS m/z 342([M]⁺).

5-(1-Bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-methoxybenzene (DI34)

1-(3,5-Dichloro-4-methoxyphenyl)-2,2,2-trifluoroethanol (DI33) wasisolated as an off white solid (0.8 g, 60%); mp 92-95° C.: ¹H NMR (400MHz, CDCl₃) δ 7.41 (s, 2H), 5.00 (m, 1H), 3.89 (s, 3H), 2.64 (m, 1H);ESIMS m/z 274 ([M]⁺). The title compound (DI34) was isolated as acolorless liquid (0.6 g, 57%).

Example 90 Preparation of1-(1-bromo-2,2,2-trifluoroethyl)-3,5-difluorobenzene (DI36)

The title compound was synthesized in two steps via1-(3,5-difluorophenyl)-2,2,2-trifluoroethanol (DI35, prepared as in Step1, Method A in Example 1; isolated as a colorless oil (0.2 g, 75%): ¹HNMR (400 MHz, CDCl₃) δ 7.05 (m, 2H), 6.88 (m, 1H), 5.06 (m, 1H), 2.66(s, 1H); ESIMS m/z 212 (Mr) and Step 2 in Example 1 and isolated (3.2 g,50%); ¹H NMR (400 MHz, CDCl₃) δ 7.05 (m, 2H), 6.86 (m, 1H), 5.03 (q,J=7.4 Hz, 1H).

The following compounds were made in accordance with the proceduresdisclosed in Example 90.

1-(1-Bromo-2,2,2-trifluoroethyl)-4-chlorobenzene (DI38)

1-(4-Chlorophenyl)-2,2,2-trifluoroethanol (DI37) was isolated as acolorless oil (5.0 g, 99%): ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.38 (m, 4H),5.05 (m, 1H), 2.55 (s, 1H); ESIMS m/z 210 ([M]⁺). The title compound(DI38) was isolated (3.0 g, 46%): ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d,J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 5.10 (q, J=7.2 Hz, 1H).

1-(1-Bromo-2,2,2-trifluoroethyl)-4-methoxybenzene (DI40)

2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanol (DI39) was isolated as a paleyellow liquid: ¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J=8.8 Hz, 2H), 6.95(m, J=8.8 Hz, 2H), 5.00 (m, 1H), 3.82 (s, 3H), 2.44 (s, 1H); ESIMS m/z206.1 ([M]⁺). The title compound (DI40) was isolated (3.8 g, 62%).

1-(1-Bromo-2,2,2-trifluoroethyl)-4-fluorobenzene (DI42)

2,2,2-Trifluoro-1-(4-fluorophenyl)ethanol (DI41) was isolated as acolorless oil (5 g, 99%): ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.45 (m, 2H),7.13-7.07 (m, 2H), 5.06 (m, 1H), 2.53 (s, 1H); ESIMS m/z 194 ([M]⁺). Thetitle compound (DI42) was prepared and carried on as crude intermediate.

1-(1-Bromo-2,2,2-trifluoroethyl)-4-methylbenzene (DI44)

2,2,2-Trifluoro-1-(p-tolyl)ethanol (DI43) was isolated as colorless oil(5.0 g, 99%): ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, J=8.0 Hz, 2H), 7.23 (d,J=8.0 Hz, 2H), 5.02 (m, 1H), 2.46 (m, 1H), 2.37 (s, 3H); ESIMS m/z 190([M]⁺). The title compound (DI44) was isolated (3.0 g, 45%).

1-(1-bromo-2,2,2-trifluoroethyl)-3-fluorobenzene (DI46)

2,2,2-Trifluoro-1-(3-fluorophenyl)ethanol (DI45) was isolated as acolorless viscous oil (2.8 g, 93%): ¹H NMR (400 MHz, CDCl₃) δ 7.41 (m,1H), 7.25 (m, 2H), 7.14 (m, 1H), 5.06 (m, 1H), 2.60 (s, 1H); ESIMS m/z194 ([M]⁺). The title compound (DI46) was isolated (2.0 g, 61%).

1-(1-Bromo-2,2,2-trifluoroethyl)-2-fluorobenzene (DI48)

2,2,2-Trifluoro-1-(2-fluorophenyl)ethanol (DI47) was isolated as acolorless oil (2.5 g, 99%): ¹H NMR (400 MHz, CDCl₃) δ 7.40 (m, 1H), 7.43(m, 1H), 7.24 (m, 1H), 7.13 (m, 1H), 5.42 (m, 1H), 2.65 (s, 1H); ESIMSm/z 194 ([M]⁺). The title compound (DI48) was isolated (2.0 g, 61%): ¹HNMR (400 MHz, CDCl₃) δ 7.61 (m, 1H), 7.40 (m, 1H), 7.23 (m, 1H), 7.10(m, 1H), 5.40 (m, 1H); GCMS m/z 255 ([M−H]⁻).

Example 91 Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5)

To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) inDMF (150 mL) were added K₂CO₃ (13.3 g, 96.7 mmol) and 1,2,4-triazole(6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at120° C. for 6 h. After completion of reaction (by TLC), the reactionmixture was diluted with H₂O and extracted with EtOAc (3×100 mL). Thecombined EtOAc layer was washed with H₂O and brine, dried over Na₂SO₄,and concentrated under reduced pressure to afford the title compound asa solid (9.0 g, 65%): mp 145-149° C.: ¹H NMR (400 MHz, CDCl₃) δ 10.08(s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d,J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]⁺).

The following compound was made in accordance with the proceduresdisclosed in Example 91.

5-Formyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (DI49)

The title compound was isolated (2.8 g, 60%); ¹H NMR (400 MHz, CDCl₃) δ10.10 (s, 1H), 8.98 (s, 1H), 8.35 (s, 1H), 8.30 (d, 1H), 8.22 (s, 1H),8.07 (d, 1H); IR (thin film) 3433, 3120, 1702, 1599, 1510 cm⁻¹.

2-Chloro-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI50)

The title compound was isolated as an off white solid (3.0 g, 40%): mp149-151° C.; ¹H NMR (400 MHz, CDCl₃) δ 10.05 (s, 1H), 8.74 (s, 1H), 8.17(s, 1H), 8.10 (s, 1H), 7.90 (m, 2H); ESIMS m/z 208.10 ([M+H]⁺).

5-Methyl-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI51)

The title compound was isolated as a white solid (0.5 g, 74%): mp109-111° C.; ¹H NMR (400 MHz, D₆-DMSO) δ 10.06 (s, 1H), 9.00 (s, 1H),8.30 (s, 1H), 7.99 (s, 1H), 7.92 (d, J=9.2 Hz, 1H), 7.69 (d, J=9.2 Hz,1H), 2.30 (s, 3H); ESIMS m/z 188.13 ([M+H]⁺).

Example 92 Preparation of5-formyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)benzonitrile (DI52)

To a stirring solution of 2-fluoro-5-formylbenzonitrile (0.5 g, 3.3mmol) in DMF (25 mL) were added K₂CO₃ (0.68 g, 4.95 mmol) and3-nitro-1,2,4 triazole (0.45 g, 4.2 mmol) and the resultant reactionmixture was stirred at RT for 14 h. After completion of reaction (TLC),the reaction mixture was diluted with water and extracted with EtOAc.The combined EtOAc layer was washed with water and brine then dried overNa₂SO₄ and concentrated under reduced pressure to afforded the titlecompound as a pale yellow solid (0.36 g, 45%): mp 170-172° C.; ¹H NMR(300 MHz, DMSO-d₆) δ 10.12 (s, 1H), 9.61 (s, 1H), 8.69 (s, 1H), 8.45 (d,J=9.3 Hz, 1H), 8.23 (d, J=9.3 Hz, 1H); ESIMS m/z 242.3 ([M−H]⁻); IR(thin film) 2238, 1705, 1551, 1314 cm⁻¹.

Example 93 Preparation of 4-(3-methyl-1H-1,2,4-triazol-1-yl)benzaldehyde(DI53)

To a stirring solution of 4-fluorobenzaldehyde (5.0 g, 40.32 mmol) inDMF (50 mL), were added K₂CO₃ (3.34 g, 40.32 mmol) and3-methyl-1,2,4-trizole (3.34 g, 40.32 mmol) and the resultant reactionmixture was stirred at RT for 4 h. After completion of the reaction(TLC), the reaction mixture was diluted with water and extracted withEtOAc (3×). The combined EtOAc layer was washed with water and brinethen dried over Na₂SO₄ and concentrated under reduced pressure toafforded the title compound as a white solid (4.1 g, 60%): mp 125-128°C.; ¹H NMR (400 MHz, CDCl₃) δ 10.05 (s, 1H), 8.76 (s, 1H), 8.02 (d, 2H),7.85 (d, 2H), 2.50 (s, 3H); ESIMS m/z 188.04 ([M+H]⁺).

The following compound was made in accordance with the proceduresdisclosed in Example 93.

4-(1H-1,2,4-triazol-1-yl)-3-(trifluoromethyl)benzaldehyde (DI54)

The title compound was isolated as white solid (1.05 g, 60%): mp 81-83°C.; ¹H NMR (400 MHz, CDCl₃) δ 10.15 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H),8.25 (d, J=7.2 Hz, 1H), 8.18 (s, 1H), 7.79 (d, J=7.2 Hz, 1H); ESIMS m/z241.0 ([M]⁺).

4-(3-nitro-1H-1,2,4-triazol-1-yl)benzaldehyde (DI55)

The title compound was isolated as pale yellow solid (0.10 g, 23%): mp159-161° C.; ¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 8.89 (s, 1H), 8.15(m, 2H), 8.00 (m, 2H); ESIMS m/z 217.11 ([M−H]⁻).

3-bromo-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI56)

The title compound was isolated as white solid (3.2 g, 51%): mp 126-128°C.; ¹H NMR (400 MHz, CDCl₃) δ 10.04 (s, 1H), 8.69 (s, 1H), 8.27 (M, 1H,8.18 (s, 1H) 7.99 (d, J=9.2 Hz, 1H), 7.76 (d, J=9.2 Hz, 1H); ESIMS m/z250.9 ([M]⁺).

5-formyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (DI57)

The title compound was isolated as white solid (0.13 g, 30%): mp147-149° C.; ¹H NMR (400 MHz, CDCl₃) δ 10.07 (s, 1H), 8.89 (s, 1H), 8.32(d, J=1.8 Hz, 1H), 8.24 (dd, J=8.6, 1.3 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H),2.54 (s, 3H); ESIMS m/z 213.09 ([M+H]⁺); IR (thin film) 2239, 1697 cm⁻¹.

3-nitro-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI58)

The title compound was isolated as pale yellow solid (3.0 g, 60%): mp116-118° C.; ¹H NMR (400 MHz, CDCl₃) δ 10.15 (s, 1H), 8.48 (s, 1H), 8.46(s, 1H), 8.26 (d, J=6.9 Hz, 1H), 8.16 (s, 1H), 7.83 (d, J=6.9 Hz, 1H);ESIMS m/z 219.00 ([M+H]⁺).

Example 94 Preparation of 1-(4-vinylphenyl)-1H-1,2,4-triazole (DI59)

To a stirred solution of 4-[1,2,4]triazol-1-yl-benzaldehyde (9.0 g, 52mmol) in 1,4-dioxane (100 mL), were added K₂CO₃ (10.76 g, 78 mmol) andmethyl triphenyl phosphonium bromide (22.2 g, 62.4 mmol) at roomtemperature. The resultant reaction mixture was heated to 70° C. for 18h. After completion of the reaction (TLC), the reaction mixture wascooled to room temperature and filtered and the obtained filtrate wasconcentrated under reduced pressure. Purification by flashchromatography (SiO₂, 100-200 mesh; 25-30% EtOAc in petroleum ether) toafforded the title compound as a white solid (5.6 g, 63%): ESIMS m/z172.09 ([M+H]⁺).

The following compound was made in accordance with the proceduresdisclosed in Example 94.

1-(2-Methyl-4-vinylphenyl)-1H-1,2,4-triazole (DI60)

The title compound was isolated as an off white solid (1.5 g, 76%): ¹HNMR (400 MHz, CDCl₃) δ 8.25 (s, 1H), 8.11 (s, 1H), 7.35 (m, 2H), 7.27(d, J=8.7 Hz, 1H), 6.74 (m, 1H), 5.82 (d, J=17.3 Hz, 1H), 5.36 (d,J=10.0 Hz, 1H), 2.25 (s, 3H); ESIMS m/z 186.14 ([M+H]⁺).

2-(1H-1,2,4-Triazol-1-yl)-5-vinylbenzonitrile (DI61)

The title compound was isolated as an off-white solid (1.40 g, 71%): mp126-129° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 8.18 (s, 1H),7.82-7.84 (m, 1H), 7.72-7.80 (m, 2H), 6.70-6.80 (dd, J=17.6, 10.8 Hz,1H), 5.90-5.95 (d, J=17.6 Hz, 1H), 5.50-5.70 (d, J=10.8 Hz, 1H); ESIMSm/z 197.03 ([M+H]⁺).

Example 95 Preparation of2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI62)

To a stirred solution of5-formyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)benzonitrile (0.36 g, 1.49mmol) in 1,4-dioxane (25 mL), were added K₂CO₃ (0.3 g, 2.2 mmol) andmethyl triphenyl phosphonium bromide (0.63 g, 1.79 mmol). The resultantreaction mixture was heated to 100° C. for 18 h. After completion of thereaction (TLC), the reaction mixture was cooled to room temperature andfiltered and the obtained filtrate was concentrated under reducedpressure. Purification by flash chromatography (SiO₂, 100-200 mesh;25-30% EtOAc in petroleum ether) to afford the title compound as a solid(0.25 g, 70%): mp 103-105° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (s, 1H),8.34 (m, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 6.87 (m,1H), 6.20 (d, J=15.7 Hz, 1H), 5.56 (d, J=11.8 Hz, 1H); ESIMS m/z 240.27([M−H]⁻); IR (thin film) 2240, 1514, 1312 cm⁻¹.

The following compound was made in accordance with the proceduresdisclosed in Example 95.

1-(3-chloro-4-vinylphenyl)-1H-1,2,4-triazole (DI63)

The title compound was isolated as an off-white solid (2.3 g, 80%): mp134-137° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.76(s, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.10 (m, 1H),5.80 (d, J=17.2 Hz, 1H), 5.47 (d, J=12.4 Hz, 1H); ESIMS m/z 206.04([M+H]⁺.

3-methyl-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI64)

The title compound was isolated as a white solid (0.6 g, 60%): mp109-111° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 7.40-7.60 (m, 4H),6.70-7.00 (dd, J=17.6, 10.8 Hz, 1H), 5.80 (d, J=17.6 Hz, 1H), 5.30 (d,J=17.6 Hz, 1H), 2.50 (s, 3H); ESIMS m/z 186.20 ([M+H]⁺).

1-(2-(trifluoromethyl)-4-vinylphenyl)-1H-1,2,4-triazole (DI65)

The title compound was isolated as a colorless oil (0.6 g, 60%): ¹H NMR(400 MHz, CDCl₃) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.72 (d,J=8.0 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 6.70-6.90 (dd, J=17.6, 10.8 Hz,1H), 5.90-6.00 (d, J=17.6 Hz, 1H), 5.50-5.80 (d, J=10.8 Hz 1H); ESIMSm/z 240.16 ([M+H]⁺).

3-nitro-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI66)

The title compound was isolated as a pale yellow solid (61 mg, 20%): mp137-139° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.60 (s, 1H), 7.68 (d, J=7.7 Hz,2H), 7.60 (d, J=8.3 Hz, 2H), 6.77 (dd, J=17.7, 10.8, 1H), 5.87 (d,J=17.7 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H); ESIMS m/z 217.28 ([M+H]⁺).

1-(2-bromo-4-vinylphenyl)-1H-1,2,4-triazole (DI67)

The title compound was isolated as a white solid (1.2 g, 40%): mp 75-77°C.; ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1H), 8.12 (s, 1H), 7.75 (s, 1H)7.42 (s, 2H), 6.70 (m, 1H), 5.83 (d, J=18 Hz, 1H), 5.42 (d, J=12 Hz,1H); ESIMS m/z 249.1 ([M]⁺).2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI68)

The title compound was isolated as an off-white solid (0.6 g, 60%): mp96-97° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H), 7.80 (s, 1H), 7.74(m, 2H), 6.73 (dd, J=17.6 Hz, 10.8 Hz, 1H), 5.88 (d, J=17.6 Hz, 1H),5.49 (d, J=10.8 Hz, 1H), 2.52 (s, 3H); ESIMS m/z 211.10 ([M+H]⁺); IR(thin film) 2229 cm⁻¹.

1-(2-nitro-4-vinylphenyl)-1H-1,2,4-triazole (DI69)

The title compound was isolated as a yellow solid (1.78 g, 60%): mp102-104° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1H), 8.12 (s, 1H), 8.02(s, 1H), 7.72-7.76 (d, J=8.0 Hz, 1H), 7.52-7.56 (d, J=17.6 Hz, 1H),6.70-6.82 (dd, J=17.6, 10.8 Hz, 1H), 5.85-6.00 (d, J=17.6 Hz, 1H),5.50-5.60 (d, J=10.8, Hz 1H); ESIMS m/z 217.0 ([M+H]⁺).

Example 96 Preparation of3-methyl-2-(1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI70)

Step 1. 5-Bromo-2-fluoro-3-methylbenzaldehyde

To a stirred solution of di-isopropyl amine (4.01 g, 39.88 mmol) in THF(20 mL) was added n-butyl lithium (1.6 M in hexane) (19.9 mL, 31.91mmol) at −78° C. slowly dropwise over the period of 10 min, the reactionmixture was stirred at −78° C. for 30 min A solution of4-bromo-1-fluoro-2-methylbenzene (5.0 g, 26.6 mmol) in THF (30.0 mL) wasadded at −78° C., and the reaction mixture was stirred for 1 h at thesame temperature. DMF (5.0 mL) was added and stirred at −78° C. foranother 30 min. The reaction was monitored by TLC; then the reactionmixture was quenched with 1N HCl solution (aq) at 0° C. The aqueouslayer was extracted with diethyl ether, washed with water and saturatedbrine solution. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to obtain the crudecompound purified by flash column chromatography (SiO₂, 100-200 mesh;eluting with 5% ethyl acetate/pet ether) to afford the title compound asa white solid (3.6 g, 64%); mp 48-50° C.: ¹H NMR (400 MHz, CDCl₃) δ 8.33(s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6,10.8 Hz, 1H), 5.92 (dd, J=17.6, 10.8 Hz, 1H), 5.52 (d, J=17.6 Hz, 1H),2.21 (s, 3H); ESIMS m/z 211.35 ([M−H]⁻).

Step 2. ((E)-5-Bromo-2-fluoro-3-methylbenzaldehyde oxime

To a stirred solution of 5-bromo-2-fluoro-3-methylbenzaldehyde (3.5 g,16.2 mmol) in ethanol (50.0 mL) were added sodium acetate (2.0 g, 24.3mmol) and hydroxylamine hydrochloride (1.69 g, 24.3 mmol) at RT. Thereaction mixture was stirred at RT for 3 h. The reaction mixture wasconcentrated on rotavapour to obtain crude compound, which was washedwith water filtered and dried under vacuum to afford the title compoundas a white solid: mp 126-127° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s,1H), 7.73 (d, J=2.4 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 2.25(s, 3H); ESIMS m/z 232.10 ([M+H]⁺).

Step 3. 5-Bromo-2-fluoro-3-methylbenzonitrile

A stirred solution of (E)-5-bromo-2-fluoro-3-methylbenzaldehyde oxime(0.5 g, 2.2 mmol) in acetic anhydride (5.0 mL) was heated to reflux for18 h. The reaction mixture was diluted with water and extracted withethyl acetate. The combined ethyl acetate layer was washed with brineand dried over Na₂SO₄ and concentrated under reduced pressure to affordthe crude compound as a light brown gummy material (0.4 g, crude): ESIMSm/z 213.82 ([M+H]⁺).

Step 4. 5-Bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (DI71)

To a stirred solution of 5-bromo-2-fluoro-3-methylbenzonitrile (1.0 g,47.716 mmol), in DMF (10.0 mL) was added potassium carbonate (1.95 g,14.14 mmol) followed by 1H-1,2,4-triazole (0.811 g, 9.433 mmol) at RT.The reaction mixture was heated to 140° C. for 18 h. The reactionmixture was cooled to RT, diluted with water and extracted with ethylacetate (2×100 mL). The combined ethyl acetate layer was washed withbrine and dried over Na₂SO₄ and concentrated under reduced pressure toafford the crude compound purified by flash column chromatography (SiO₂,100-200 mesh; eluting with 30% ethyl acetate/pet ether) to afford thetitle compound as a pink solid (0.6 g, 49%): ¹H NMR (400 MHz, CDCl₃) δ8.39 (s, 1H), 8.23 (s, 1H), 7.91 (d, J=2.4 Hz, 2H), 2.21 (s, 3H), ESIMSm/z 262.57 ([M+H]⁺); IR (thin film) 2231, 554 cm⁻¹.

Step 5. 3-Methyl-2-(1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI70)

A mixture of 5-bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.6g, 2.3 mmol), potassium carbonate (0.95 g, 6.87 mmol), vinyl boronicanhydride (0.82 g, 3.43 mmol) and triphenylphosphine (0.13 g, 0.114mmol) in toluene (20.0 mL) were stirred and degassed with argon for 30min. The reaction mixture was heated to reflux for 18 h. The reactionmixture was cooled to RT, diluted with water and extracted with ethylacetate (2×100 mL). The combined ethyl acetate layer was washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure toafford the crude compound that was purified by flash columnchromatography (SiO₂, 100-200 mesh; eluting with 30% ethyl acetate/petether) to afford the title compound as a pink solid (0.25 g, 52%): ¹HNMR (400 MHz, CDCl₃) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60(s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (d, J=17.6, 1H), 5.52 (d,J=10.8 Hz, 1H), 2.21 (s, 3H), ESIMS m/z 211.35 ([M+H]⁺); IR (thin film)2236, 1511 cm⁻¹.

The following compound was made in accordance with the proceduresdisclosed in Steps 4 and 5 of Example 96.

1-(2-fluoro-4-vinylphenyl)-1H-1,2,4-triazole (DI72)

1-(4-Bromo-2-fluorophenyl)-1H-1,2,4-triazole (DI73) was isolated as apale yellow solid (3.0 g, 75%): mp 113-116° C.; ¹H NMR (400 MHz, CDCl₃)δ 8.69 (s, 1H), 8.13 (m, 2H), 7.50 (m, 1H), 7.21 (m, 1H); ESIMS m/z241.93 ([M]⁺). The title compound (DI72) was isolated as a yellow solid(1.0 g, 71%): mp 67-70° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.13(s, 1H), 7.94 (m, 1H), 7.41 (m, 1H), 7.24 (s, 1H), 6.75 (dd, J=17.6,10.8 Hz, 1H), 5.81 (d, J=17.6 Hz, 1H), 5.37 (d, J=10.8 Hz, 1H); ESIMSm/z 190.00 ([M+H]⁺).

Example 119 Preparation of1-(1-(4-vinylphenyl)-1H-1,2,4-triazol-5-yl)ethanone (DI78)

To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C.and stirred for 30 min. To this N-methoxy-N-methyl acetamide in THF(0.66 g, 6.4 mmol) was added and the resultant reaction mixture wasstirred at RT for 16 h. The reaction mixture was quenched with asaturated aqueous NH₄Cl solution and extracted with EtOAc (3×50 mL). Thecombined EtOAc layer was washed with brine and dried over sodiumsulphate and concentrated under reduced pressure. The crude compound waspurified by flash chromatography (SiO₂, 100-200 mesh, 40% EtOAc in Petether) to afford the title compound as an off white solid (280 mg, 23%):mp 97-98° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.50 (d, 2H), 7.38(d, 2H), 6.68 (dd, 1H), 5.85 (d, 1H), 5.38 (d, 1H), 2.75 (s, 3H); ESIMSm/z 214.14 ([M+H]⁺).

Example 120 Preparation ofcyclopropyl(1-(4-vinylphenyl)-1H-1,2,4-triazol-5-yl)methanone (DI79)

To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C.and stirred for 30 min. To this N-methoxy N-methylcyclopropoxide in THF(0.82 g, 6.4 mmol) was added and the resultant reaction mixture wasstirred at RT for 16 h. The reaction mixture was quenched with asaturated aqueous NH₄Cl solution and extracted with EtOAc (3×25 mL). Thecombined EtOAc layer was washed with brine and dried over sodiumsulphate and concentrated under reduced pressure. The crude compound waspurified by flash chromatography (SiO₂, 100-200 mesh, 40% EtOAc in Petether) to afford the title compound as an off white solid (420 mg, 30%):mp 90-91° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.50 (d, J=7.8 Hz,2H), 7.38 (d, J=7.8 Hz, 2H), 6.75 (dd, J=16.3, 10.7 Hz, 1H), 5.81 (d,J=16.3 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 3.22 (m, 1H), 1.27 (m, 2H),1.18 (m, 2H); ESIMS m/z 240.18 ([M+H]⁺); IR (thin film) 2922, 1630 cm⁻¹.

Example 121 Preparation of5-(methylthio)-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI80)

To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8mmol) in 50 mL of THF, was added n-BuLi (0.41 g, 6.4 mmol) at −78° C.and stirred for 30 min. To this dimethyldisulfide in THF (0.6 g, 6.43mmol) was added and the resultant reaction mixture was stirred at RT for16 h. The reaction mixture was quenched with a saturated aqueous NH₄Clsolution and extracted with EtOAc (3×25 mL). The combined EtOAc layerwas washed with brine and dried over sodium sulphate and concentratedunder reduced pressure. The crude compound was purified by flashchromatography (SiO₂, 100-200 mesh, 40% EtOAc in Pet ether) to affordthe title compound as an off white solid (0.6 g, 48%): mp 68-70° C.; ¹HNMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.05 (m, 4H), 6.75 (dd, J=16.4,10.7 Hz, 1H), 5.81 (d, J=16.4 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 2.73 (s,3H); ESIMS m/z 218.09 ([M+H]⁺).

Example 122 Preparation of 5-methyl-1-(4-vinylphenyl)-1H-1,2,4-triazole(DI81)

To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (0.5 g,2.9 mmol) in 10 mL of THF, was added n-BuLi (0.22 g, 3.5 mmol) at −78°C. and stirred for 30 min. To this methyl iodide in THF (0.50 g, 3.5mmol) was added and the resultant reaction mixture was stirred at RT for16 h. The reaction mixture was quenched with a saturated aqueous NH₄Clsolution and extracted with EtOAc (3×25 mL). The combined EtOAc layerwas washed with brine and dried over sodium sulphate and concentratedunder reduced pressure The crude compound was purified by flashchromatography (SiO₂, 100-200 mesh, 40% EtOAc in Pet ether) afford thetitle compound as a pale brown liquid (250 mg, 46%): ¹H NMR (400 MHz,CDCl₃) δ 7.93 (s, 1H), 7.55 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 2H), 6.76(dd, J=18, 11 Hz, 1H), 5.83 (d, J=18 Hz, 1H), 5.38 (d, J=11 Hz, 1H),2.55 (s, 3H); ESIMS m/z 186.13 ([M+H]⁺); IR (thin film) 1517, 1386,1182, 847 cm⁻¹.

Example 97 Preparation of(E)-1-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-1H-1,2,4-triazole(DC1)

To a stirred solution of1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichloro-benzene (2.0 g, 6.51mmol) in 1,2-dichlorobenzene (25 mL), were added1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (2.22 g, 13.0 mmol), CuCl (64 mg,0.65 mmol) and 2,2-bipyridyl (0.2 g, 1.3 mmol). The resultant reactionmixture was degassed with argon for 30 min, then stirred at 180° C. for24 h. After completion of reaction (TLC), the reaction mixture wascooled to RT and filtered and the filtrate concentrated under reducedpressure. Purification by flash chromatography (SiO₂, 100-200 mesh;25-30% EtOAc in petroleum ether) afforded the title compound as anoff-white solid (0.8 g, 32%): mp 93-97° C.; ¹H NMR (300 MHz, CDCl₃) δ8.56 (s, 1H), 8.11 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz,2H), 7.38 (t, J=1.8 Hz, 1H), 7.29 (s, 2H), 6.62 (d, J=15.6 Hz, 1H), 6.42(dd, J=15.6, 8.2 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 398.05 ([M+H]⁺).

Compounds DC2-DC37, DC44, DC45, DC47-49, DC50, DC51, DC54, DC58, DC60,DC62, and DC63-DC67 in Table 1 were made in accordance with theprocedures disclosed in Example 97.

Example 98 Preparation of(E)-2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzonitrile(DC40)

To a stirred solution of2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (0.9 g, 3.7 mmol)in 1,2-dichlorobenzene (10 mL), were added5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (2.5 g, 7.5mmol), CuCl (73 mg, 0.74 mmol) and 2,2-bipyridyl (0.23 g, 1.49 mmol) andthe resultant reaction mixture was degassed with argon for 30 min andthen stirred at 180° C. for 14 h. After completion of the reaction(TLC), the reaction mixture was cooled to RT and filtered and thefiltrate was concentrated under reduced pressure. Purification by flashchromatography (SiO₂, 100-200 mesh, 25-30% EtOAc in Pet ether) affordedthe title compound as a off white solid (0.9 g, 50%): mp 70-73° C.; ¹HNMR (300 MHz, CDCl₃) δ 8.86 (s, 1H), 7.88 (m, 3H), 7.44 (s, 2H), 6.67(d, J=16.0 Hz, 1H), 6.56 (dd, J=16.0, 7.6 Hz, 1H), 4.19 (m, 1H); ESIMSm/z 436.11 ([M−2H]⁻).

Example 99 Preparation of(E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzonitrile(DC41)

To a stirred solution of(E)-2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile(0.6 g, 1.2 mmol) in MeOH (10 mL), were added Zn dust (0.39 g, 5.98mmol) and sat. aq NH₄Cl solution (5 mL) and the resultant reactionmixture was stirred at RT for 2 h. After completion of the reaction(TLC), the reaction mass was concentrated under reduced pressure. Thereaction mass was diluted with DCM, filtered through a celite bed, andthe obtained filtrate concentrated under reduced pressure to afford thetitle compound as a solid (0.5 g, 89%): mp 72-75° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 8.72 (s, 1H), 8.26 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.91 (s,2H), 7.77 (d, J=8.4 Hz, 1H), 6.42 (dd, J=15.6, 9.2 Hz, 1H), 6.83 (d,J=15.6 Hz, 1H), 5.87 (s, 2H), 4.89 (m, 1H); ESIMS m/z 469.95 ([M−H]⁻).

Compound DC38 in Table 1 was made in accordance with the proceduresdisclosed in Example 99. Also, compound DC55 in Table 1 was made fromcompound DC54 in accordance with the procedures disclosed in Example 99,with the exception of using ammonium formate in place of ammoniumchloride.

Example 100 Preparation of(E)-N-(1-(2-cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-1H-1,2,4-triazol-3-yl)-N-(cyclopropanecarbonyl)cyclopropanecarboxamide(DC42)

To a stirred solution of(E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile(0.1 g, 0.21 mmol) in DCM at RT, was added cyclopropylcarbonyl chloride(0.045 g, 0.42 mmol) and the reaction mixture was stirred for 2 h at RT.The reaction mixture was diluted with DCM and washed with water andbrine and dried over Na₂SO₄. Concentration under reduced pressure andpurification by preparative HPLC afforded the title compound as a solid(0.09 g, 79%): mp 104-107° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.78 (s, 2H),7.83 (s, 1H), 7.80 (m, 2H), 7.42 (s, 2H), 6.65 (d, J=16.4 Hz, 1H), 6.51(dd, J=7.6, 8.0 Hz, 1H), 4.17 (m, 1H), 2.16 (m, 2H), 1.25 (m, 4H), 1.00(m, 4H); ESIMS m/z 609.98 ([M+H]⁺); IR (thin film) 2234, 1714, 1114, 807cm⁻¹.

Example 101 Preparation of(E)-N-(1-(2-cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-1H-1,2,4-triazol-3-y0cyclopropanecarboxamide(DC43)

To a stirred solution of(E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile(0.15 g, 0.31 mmol) in DCM at 0° C., were added triethylamine (0.1 g, 1mmol) and cyclopropylcarbonyl chloride (0.04 g, 0.38 mmol) and thereaction mixture was stirred for 1 h at 0° C. The reaction mixture wasdiluted with DCM and washed with water and brine and dried over Na₂SO₄.Concentration under reduced pressure and purification by columnchromatography (SiO₂, 100-200 mesh) afforded the title compound as asolid (66 mg, 34%): mp 109-112° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 10.94(br s, 1H), 8.36 (s, 1H), 8.08 (m, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.84 (d,J=8.4 Hz, 1H), 7.13 (dd, J=15.6, 9.2 Hz, 1H), 6.87 (d, J=15.6 Hz, 1H),4.92 (m, 1H), 1.99 (br s, 1H), 0.82 (s, 4H); ESIMS m/z 540.04 ([M+H]⁺);IR (thin film) 3233, 2233, 1699, 1114, 807 cm⁻¹.

Compound DC39 in Table 1 was made in accordance with the proceduresdisclosed in Example 101.

Example 102 Preparation of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethanone(DI74)

To a stirred solution of 4-bromoacetophenone (10 g, 50 mmol) in DMF (100mL), were added 1,2,4-triazole (5 g, 75 mmol), Cs₂CO₃ (32.6 g, 100.5mmol) and CuI (1.4 g, 10.1 mmol) and the resultant reaction mixture wasrefluxed for 48 h. After completion of the reaction (by TLC), thereaction mixture was cooled to RT and diluted with water (200 mL) andextracted with EtOAc. The combined organic layer was washed with brineand dried over Na₂SO₄ and concentrated under reduced pressure.Purification by washing with diethyl ether afforded the title compoundas a solid (5 g, 96%): ¹H NMR (400 MHz, CDCl₃) δ 8.71 (s, 1H), 8.16, (s,1H), 8.13 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.6 Hz, 2H), 2.66 (s, 3H); ESIMSm/z 186.02 ([M−H]⁻).

Example 103 Preparation of1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one(DI75)

Step 1. 1-(4-(1-(trimethylsilyloxy)vinyl)phenyl)-1H-1,2,4-triazole(DI76)

To a stirred solution of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethanone(4.5 g, 24.0 mmol) in DCM at 0° C., were added TEA (3.7 g, 36.1 mmol)and trimethylsilyl trifluoromethanesulfonate (8 g, 36 mmol) and theresultant reaction mixture was stirred for 1 h. The reaction mixture wasquenched with a mixture of sat aq sodium bicarbonate solution and ether.The ether layer and was separated, washed with brine, dried over Na₂SO₄and concentrated under reduced pressure to afford the title compound(5.5 g) which was taken directly to next step.

Step 2.1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one(DI75)

To a stirred solution of1-(4-(1-(trimethylsilyloxy)vinyl)phenyl)-1H-1,2,4-triazole (6 g, 23mmol) and 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichlorobenzene (7.1 g,34.7 mmol) in 1,2-dichlorobenzene (30 mL) was degassed with argon. Tothis CuCl (0.23 g, 2.31 mmol) and 2,2-bipyridyl (0.73 g, 4.63 mmol) wasadded to the above reaction mixture and the resultant reaction mixturewas heated to 180° C. for 18 h. After completion of the reaction (byTLC), the reaction mixture was absorbed onto silica gel and purified bycolumn chromatography (SiO2; 10% EtOAc in petroleum ether) to affordtitle compound as a solid (3 g, 31%): ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s,1H), 8.15 (s, 1H), 8.10 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.33(m, 1H), 7.30 (m, 2H), 4.20 (m, 1H), 3.63 (m, 2H); ESIMS m/z 412. 14([M−H]⁻).

Example 104 Preparation of2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5-trifluoropentan-2-ol(DI77)

To a solution of1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one(300 mg, 0.726 mmol) in THF cooled to 0° C. was added methylmagnesiumbromide (450 mg, 5 mmol) drop wise. The reaction was stirred for 3 h at0° C., then the reaction mixture was quenched with sat aq NH₄Cl solutionand extracted with ethyl acetate. The combined EtOAc layer was washedwith water and brine, dried over Na₂SO₄ and concentrated under reducedpressure. Purification by column chromatography (SiO₂, 100-200 mesh;20%-25% EtOAc in petroleum ether) afforded the title compound as a solid(100 mg, 32%): ¹H NMR (400 MHz, CDCl₃) δ two diastereoisomers 8.58 (s,1H, minor), 8.48 (s, 1H, major), 8.13 (s, 1H, minor), 8.09 (s, 1H,major), 7.70 (d, J=9.0 Hz, 2H, minor), 7.53 (d, J=9.0 Hz, 2H, minor),7.40 (d, J=9.0 Hz, 2H, major), 7.31 (m, 1H, minor), 7.27 (d, J=9.0 Hz,2H, major), 7.20 (m, 2H, minor), 7.01 (m, 1H, major), 6.75 (m, 2H,major), 350 (m, 1H), 2.50 (m, 2H), 1.56 (s, 3H, major), 1.54 (s, 3H,minor); ESIMS m/z 430.05 ([M+H]⁺).

Example 105 Preparation of(E)-1-(4-(4-(3,5-dichlorophenyl)-5,5,5-trifluoropent-2-en-2-yl)phenyl)-1H-1,2,4-triazole(DC68)

To a solution of2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5-trifluoropentan-2-ol(100 mg, 0.233 mmol) in toluene was added a catalytic amount ofp-toluenesulfonic acid (PTSA) and the water was removed by azeotropicdistillation over the course of 12 h. The reaction mixture was cooled toroom temperature and dissolved in ethyl acetate. The solution was washedwith sat aq NaHCO₃ solution and brine, dried over Na₂SO₄ andconcentrated under reduced pressure. Purification by columnchromatography (SiO₂, 100-200 mesh; 20%-25% EtOAc in petroleum ether)afforded the title compound as a solid (30 mg, 31%).

Example 123 Preparation of(E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzaldehyde(DC52)

To a stirred solution of(E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile(0.3 g, 0.71 mmol) in toluene (10 mL) at −78° C. was added dropwisediisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 0.85mL), and the reaction mixture was stirred at −78° C. for 20 min. Thereaction mixture was quenched with the addition of 1 N HCl solution,then the aqueous layer was extracted with EtOAc (2×). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byflash column chromatography (SiO₂; 50% EtOAc/Pet ether) to afford thetitle compound as a yellow oil.

Compound DC53 in Table 1 was made in accordance with the proceduresdisclosed in Example 123.

Example 124 Preparation of(E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-methyl-2-(1H-1,2,4-triazol-1-yl)aniline(DC57)

To a stirred solution of(E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)aniline(0.3 g, 0.7 mmol) in DCM (10 mL) was added triethylamine (0.155 mL, 1.09mmol) and methyl iodide (0.124 g, 0.873 mmol). The reaction was stirredat RT for 18 h. The DCM layer was washed with water and brine, driedover Na₂SO₄ and concentrated under reduced pressure. The crude compoundwas purified by flash column chromatography (SiO₂; 50% EtOAc/Pet ether)to afford the title compound as a yellow semi-solid (0.07 g, 70%).

Example 125 Preparation of(E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzoicacid (DC61)

A solution of (E)-ethyl5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzoate(0.2 g, 0.4 mmol) in 6 N HCl (10 mL) was stirred at 100° C. for 18 h.The reaction was cooled to RT, resulting in a white solid precipitate.The precipitate was filtered to afford the title compound as a whitesolid (0.12 g, 60%).

Example 126 Preparation of(Z)-5-((E)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N′-hydroxy-2-(1H-1,2,4-triazol-1-yl)benzimidamide(DC59)

A solution of(E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile(0.3 g, 0.71 mmol), sodium acetate (0.087 g, 1.065 mmol) andhydroxylammonium chloride (0.072 g, 1.065 mmol) in 9:1 ethanol/watermixture (10 mL) was stirred at 70° C. for 8 h. The reaction was cooledto RT, and the ethanol was evaporated. The residue was dissolved inwater and extracted with EtOAc (2×). The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to afford the title compound as an off white solid.

Example 127 Preparation of(E)-1-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-methoxybut-1-en-1-yl)phenyl)-1H-1,2,4-triazole(DC70)

Step 1.(E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(3,5-dichlorophenyl)prop-2-en-1-one

To a solution of 1-(3,5-dichlorophenyl)ethanone (0.5 g, 2.6 mmol) inethanol (20 mL) was added 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (0.46 g,2.65 mmol) and the reaction was cooled to 0° C. Sodium hydroxide (0.22g, 5.29 mmol) in water (10 mL) was then added and the reaction wasallowed to stir for 2 h at 0° C. The reaction was extracted with EtOAcand the combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure to afford the title compound (0.149 g, 17%):);ESIMS m/z 430.05 ([M+H]⁺) 344.08

Step 2.(E)-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-2-(3,5-dichlorophenyl)-1,1,1-trifluorobut-3-en-2-ol(DC69)

To a solution of(E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(3,5-dichlorophenyl)prop-2-en-1-one(1 g, 3 mmol) in THF (150 mL) was added trifluoromethyltrimethylsilane(0.517 g, 3.644 mmol) and tetra-n-butylammonium fluoride (TBAF) (1.0 M,1 mL) at 0° C. The reaction was slowly warmed to RT and allowed to stirfor 2 h. The reaction was then cooled to 0° C. and 5 M HCl solution wasadded and the reaction was stirred for an additional 4 h at RT. Thereaction was extracted with DCM and the combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by flash column chromatography (SiO₂; 25%EtOAc/hexanes) to afford the title compound as an off-white solid (0.3g, 25%).

Step 3.(E)-1-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-methoxybut-1-en-1-yl)phenyl)-1H-1,2,4-triazole(DC70)

To a solution of(E)-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-2-(3,5-dichlorophenyl)-1,1,1-trifluorobut-3-en-2-ol(0.15 g, 0.36 mmol) in THF (5 mL) was added NaH (60%, 10 mg, 0.44 mmol)at 0° C. The reaction was allowed to stir at 0° C. for 30 min, thenmethyl iodide (61 mg, 0.44 mmol) was added slowly and the reaction waswarmed to RT and allowed to stir for 4 h. The reaction was quenched withaq NH₄Cl solution and extracted with DCM. The combined organic layerswere dried over Na₂SO₄ and concentrated under reduced pressure to affordthe title compound as an off-white solid (55 mg, 35%).

Example A Bioassays on Beet Armyworm (“BAW”) and Corn Earworm (“CEW”)

BAW has few effective parasites, diseases, or predators to lower itspopulation. BAW infests many weeds, trees, grasses, legumes, and fieldcrops. In various places, it is of economic concern upon asparagus,cotton, corn, soybeans, tobacco, alfalfa, sugar beets, peppers,tomatoes, potatoes, onions, peas, sunflowers, and citrus, among otherplants. CEW is known to attack corn and tomatoes, but it also attacksartichoke, asparagus, cabbage, cantaloupe, collards, cowpeas, cucumbers,eggplant, lettuce, lima beans, melon, okra, peas, peppers, potatoes,pumpkin, snap beans, spinach, squash, sweet potatoes, and watermelon,among other plants. CEW is also known to be resistant to certaininsecticides. Consequently, because of the above factors control ofthese pests is important. Furthermore, molecules that control thesepests are useful in controlling other pests.

Certain molecules disclosed in this document were tested against BAW andCEW using procedures described in the following examples. In thereporting of the results, the “BAW & CEW Rating Table” was used (SeeTable Section).

Bioassays on BAW (Spodoptera exigua)

Bioassays on BAW were conducted using a 128-well diet tray assay. one tofive second instar BAW larvae were placed in each well (3 mL) of thediet tray that had been previously filled with 1 mL of artificial dietto which 50 μg/cm² of the test compound (dissolved in 50 μL of 90:10acetone-water mixture) had been applied (to each of eight wells) andthen allowed to dry. Trays were covered with a clear self-adhesivecover, and held at 25° C., 14:10 light-dark for five to seven days.Percent mortality was recorded for the larvae in each well; activity inthe eight wells was then averaged. The results are indicated in thetable entitled “Table 3: Assay Results” (See Table Section).

Bioassays on CEW (Helicoverpa zea)

Bioassays on CEW were conducted using a 128-well diet tray assay. one tofive second instar CEW larvae were placed in each well (3 mL) of thediet tray that had been previously filled with 1 mL of artificial dietto which 50 μg/cm² of the test compound (dissolved in 50 μL of 90:10acetone-water mixture) had been applied (to each of eight wells) andthen allowed to dry. Trays were covered with a clear self-adhesivecover, and held at 25° C., 14:10 light-dark for five to seven days.Percent mortality was recorded for the larvae in each well; activity inthe eight wells was then averaged. The results are indicated in thetable entitled “Table 3: Assay Results” (See Table Section).

Example B Bioassays on Green Peach Aphid (“GPA”) (Myzus persicae)

GPA is the most significant aphid pest of peach trees, causing decreasedgrowth, shriveling of the leaves, and the death of various tissues. Itis also hazardous because it acts as a vector for the transport of plantviruses, such as potato virus Y and potato leafroll virus to members ofthe nightshade/potato family Solanaceae, and various mosaic viruses tomany other food crops. GPA attacks such plants as broccoli, burdock,cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce,macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress, andzucchini, among other plants. GPA also attacks many ornamental cropssuch as carnation, chrysanthemum, flowering white cabbage, poinsettia,and roses. GPA has developed resistance to many pesticides.

Certain molecules disclosed in this document were tested against GPAusing procedures described in the following example. In the reporting ofthe results, the “GPA Rating Table” was used (See Table Section).

Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) trueleaves, were used as test substrate. The seedlings were infested with20-50 GPA (wingless adult and nymph stages) one day prior to chemicalapplication. Four pots with individual seedlings were used for eachtreatment. Test compounds (2 mg) were dissolved in 2 mL ofacetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm testcompound. The stock solutions were diluted 5× with 0.025% Tween 20 inH₂O to obtain the solution at 200 ppm test compound. A hand-heldaspirator-type sprayer was used for spraying a solution to both sides ofcabbage leaves until runoff. Reference plants (solvent check) weresprayed with the diluent only containing 20% by volume ofacetone/methanol (1:1) solvent. Treated plants were held in a holdingroom for three days at approximately 25° C. and ambient relativehumidity (RH) prior to grading. Evaluation was conducted by counting thenumber of live aphids per plant under a microscope. Percent Control wasmeasured by using Abbott's correction formula (W. S. Abbott, “A Methodof Computing the Effectiveness of an Insecticide” J. Econ. Entomol. 18(1925), pp. 265-267) as follows.

Corrected % Control=100*(X−Y)/X

-   -   where    -   X=No. of live aphids on solvent check plants and    -   Y=No. of live aphids on treated plants

The results are indicated in the table entitled “Table 3: Assay Results”(See Table Section).

Pesticidally Acceptable Acid Addition Salts, Salt Derivatives, Solvates,Ester Derivatives, Polymorphs, Isotopes and Radionuclides

Molecules of Formula One may be formulated into pesticidally acceptableacid addition salts. By way of a non-limiting example, an amine functioncan form salts with hydrochloric, hydrobromic, sulfuric, phosphoric,acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic,succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic,benzenesulfonic, methanesulfonic, ethanesulfonic,hydroxymethanesulfonic, and hydroxyethanesulfonic acids. Additionally,by way of a non-limiting example, an acid function can form saltsincluding those derived from alkali or alkaline earth metals and thosederived from ammonia and amines. Examples of preferred cations includesodium, potassium, and magnesium.

Molecules of Formula One may be formulated into salt derivatives. By wayof a non-limiting example, a salt derivative can be prepared bycontacting a free base with a sufficient amount of the desired acid toproduce a salt. A free base may be regenerated by treating the salt witha suitable dilute aqueous base solution such as dilute aqueous sodiumhydroxide (NaOH), potassium carbonate, ammonia, and sodium bicarbonate.As an example, in many cases, a pesticide, such as 2,4-D, is made morewater-soluble by converting it to its dimethylamine salt.

Molecules of Formula One may be formulated into stable complexes with asolvent, such that the complex remains intact after the non-complexedsolvent is removed. These complexes are often referred to as “solvates.”However, it is particularly desirable to form stable hydrates with wateras the solvent.

Molecules of Formula One may be made into ester derivatives. These esterderivatives can then be applied in the same manner as the inventiondisclosed in this document is applied.

Molecules of Formula One may be made as various crystal polymorphs.Polymorphism is important in the development of agrochemicals sincedifferent crystal polymorphs or structures of the same molecule can havevastly different physical properties and biological performances.

Molecules of Formula One may be made with different isotopes. Ofparticular importance are molecules having ²H (also known as deuterium)in place of ¹H.

Molecules of Formula One may be made with different radionuclides. Ofparticular importance are molecules having ¹⁴C.

Stereoisomers

Molecules of Formula One may exist as one or more stereoisomers. Thus,certain molecules can be produced as racemic mixtures. It will beappreciated by those skilled in the art that one stereoisomer may bemore active than the other stereoisomers. Individual stereoisomers maybe obtained by known selective synthetic procedures, by conventionalsynthetic procedures using resolved starting materials, or byconventional resolution procedures. Certain molecules disclosed in thisdocument can exist as two or more isomers. The various isomers includegeometric isomers, diastereomers, and enantiomers. Thus, the moleculesdisclosed in this document include geometric isomers, racemic mixtures,individual stereoisomers, and optically active mixtures. It will beappreciated by those skilled in the art that one isomer may be moreactive than the others. The structures disclosed in the presentdisclosure are drawn in only one geometric form for clarity, but areintended to represent all geometric forms of the molecule.

Combinations

Molecules of Formula One may also be used in combination (such as, in acompositional mixture, or a simultaneous or sequential application) withone or more compounds having acaricidal, algicidal, avicidal,bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal,nematicidal, rodenticidal, or virucidal properties. Additionally, themolecules of Formula One may also be used in combination (such as, in acompositional mixture, or a simultaneous or sequential application) withcompounds that are antifeedants, bird repellents, chemosterilants,herbicide safeners, insect attractants, insect repellents, mammalrepellents, mating disrupters, plant activators, plant growthregulators, or synergists. Examples of such compounds in the abovegroups that may be used with the Molecules of Formula Oneare—(3-ethoxypropyl)mercury bromide, 1,2-dichloropropane,1,3-dichloropropene, 1-methylcyclopropene, 1-naphthol,2-(octylthio)ethanol, 2,3,5-tri-iodobenzoic acid, 2,3,6-TBA,2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6-TBA-potassium,2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2-butoxypropyl, 2,4,5-T-2-ethylhexyl,2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-T-butotyl,2,4,5-T-butyl, 2,4,5-T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl,2,4,5-T-methyl, 2,4,5-T-pentyl, 2,4,5-T-sodium,2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4-D,2,4-D-2-butoxypropyl, 2,4-D-2-ethylhexyl, 2,4-D-3-butoxypropyl,2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium,2,4-DB-isoctyl, 2,4-DB-potassium, 2,4-DB-sodium, 2,4-D-butotyl,2,4-D-butyl, 2,4-D-diethylammonium, 2,4-D-dimethylammonium,2,4-D-diolamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4-D-ethyl,2,4-D-heptylammonium, 2,4-D-isobutyl, 2,4-D-isoctyl, 2,4-D-isopropyl,2,4-D-isopropylammonium, 2,4-D-lithium, 2,4-D-meptyl, 2,4-D-methyl,2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,4-D-propyl, 2,4-D-sodium,2,4-D-tefuryl, 2,4-D-tetradecylammonium, 2,4-D-triethylammonium,2,4-D-tris(2-hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP,2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP,4-aminopyridine, 4-CPA, 4-CPA-potassium, 4-CPA-sodium, 4-CPB, 4-CPP,4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate,8-phenylmercurioxyquinoline, abamectin, abscisic acid, ACC, acephate,acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole,acibenzolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl,acifluorfen-sodium, aclonifen, acrep, acrinathrin, acrolein,acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc, alachlor,alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin,allethrin, allicin, allidochlor, allosamidin, alloxydim,alloxydim-sodium, allyl alcohol, allyxycarb, alorac, alpha-cypermethrin,alpha-endosulfan, ametoctradin, ametridione, ametryn, amibuzin,amicarbazone, amicarthiazol, amidithion, amidoflumet, amidosulfuron,aminocarb, aminocyclopyrachlor, aminocyclopyrachlor-methyl,aminocyclopyrachlor-potassium, aminopyralid, aminopyralid-potassium,aminopyralid-tris(2-hydroxypropyl)ammonium, amiprofos-methyl,amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole,ammonium sulfamate, ammonium α-naphthaleneacetate, amobam, ampropylfos,anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone,antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam,asulam-potassium, asulam-sodium, athidathion, atraton, atrazine,aureofungin, aviglycine, aviglycine hydrochloride, azaconazole,azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos-ethyl,azinphos-methyl, aziprotryne, azithiram, azobenzene, azocyclotin,azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate,barium polysulfide, barthrin, BCPC, beflubutamid, benalaxyl,benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolin-ethyl,benazolin-potassium, bencarbazone, benclothiaz, bendiocarb, benfluralin,benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos,benquinox, bensulfuron, bensulfuron-methyl, bensulide, bensultap,bentaluron, bentazone, bentazone-sodium, benthiavalicarb,benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox,benzadox-ammonium, benzalkonium chloride, benzamacril,benzamacril-isobutyl, benzamorf, benzfendizone, benzipram,benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid,benzoximate, benzoylprop, benzoylprop-ethyl, benzthiazuron, benzylbenzoate, benzyladenine, berberine, berberine chloride, beta-cyfluthrin,beta-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, bifenox,bifenthrin, bifujunzhi, bilanafos, bilanafos-sodium, binapacryl,bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin,bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac,bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen,blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid,brassinolide, brassinolide-ethyl, brevicomin, brodifacoum,brofenvalerate, brofluthrinate, bromacil, bromacil-lithium,bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos,bromoacetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT,bromofenoxim, bromophos, bromophos-ethyl, bromopropylate, bromothalonil,bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxyniloctanoate, bromoxynil-potassium, brompyrazon, bromuconazole, bronopol,bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundymixture, busulfan, butacarb, butachlor, butafenacil, butamifos,butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron,butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin,butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos,cafenstrole, calcium arsenate, calcium chlorate, calcium cyanamide,calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor,captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam,carbendazim, carbendazim benzenesulfonate, carbendazim sulfite,carbetamide, carbofuran, carbon disulfide, carbon tetrachloride,carbophenothion, carbosulfan, carboxazole, carboxide, carboxin,carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartaphydrochloride, carvacrol, carvone, CDEA, cellocidin, CEPC, ceralure,Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone,chlomethoxyfen, chloralose, chloramben, chloramben-ammonium,chloramben-diolamine, chloramben-methyl, chloramben-methylammonium,chloramben-sodium, chloramine phosphorus, chloramphenicol,chloraniformethan, chloranil, chloranocryl, chlorantraniliprole,chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside,chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane,chlordecone, chlordimeform, chlordimeform hydrochloride,chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac,chlorfenac-ammonium, chlorfenac-sodium, chlorfenapyr, chlorfenazole,chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide,chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren,chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon,chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequatchloride, chlomidine, chlornitrofen, chlorobenzilate,chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron,chloroneb, chlorophacinone, chlorophacinone-sodium, chloropicrin,chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron,chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim,chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos,chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal,chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos,chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II,cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide,cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop,clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium,clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone,clomeprop, cloprop, cloproxydim, clopyralid, clopyralid-methyl,clopyralid-olamine, clopyralid-potassium,clopyralid-tris(2-hydroxypropyl)ammonium, cloquintocet,cloquintocet-mexyl, cloransulam, cloransulam-methyl, closantel,clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA,codlelure, colophonate, copper acetate, copper acetoarsenite, copperarsenate, copper carbonate, basic, copper hydroxide, copper naphthenate,copper oleate, copper oxychloride, copper silicate, copper sulfate,copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl,coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol,crimidine, crotamiton, crotoxyphos, crufomate, cryolite, cue-lure,cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide,cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate,cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide,cyclethrin, cycloate, cycloheximide, cycloprate, cycloprothrin,cyclosulfamuron, cycloxaprid, cycloxydim, cycluron, cyenopyrafen,cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl,cyhalothrin, cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil,cyometrinil, cypendazole, cypermethrin, cyperquat, cyperquat chloride,cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil,cyprofuram, cypromid, cyprosulfamide, cyromazine, cythioate, daimuron,dalapon, dalapon-calcium, dalapon-magnesium, dalapon-sodium, daminozide,dayoutong, dazomet, dazomet-sodium, DB CP, d-camphor, DCIP, DCPTA, DDT,debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor,deltamethrin, demephion, demephion-O, demephion-S, demeton,demeton-methyl, demeton-O, demeton-O-methyl, demeton-S,demeton-S-methyl, demeton-S-methylsulphon, desmedipham, desmetryn,d-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos,diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate,dicamba, dicamba-diglycolamine, dicamba-dimethylammonium,dicamba-diolamine, dicamba-isopropylammonium, dicamba-methyl,dicamba-olamine, dicamba-potassium, dicamba-sodium, dicamba-trolamine,dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone,dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl,dichlormate, dichlormid, dichlorophen, dichlorprop,dichlorprop-2-ethylhexyl, dichlorprop-butotyl,dichlorprop-dimethylammonium, dichlorprop-ethylammonium,dichlorprop-isoctyl, dichlorprop-methyl, dichlorprop-P,dichlorprop-P-2-ethylhexyl, dichlorprop-P-dimethylammonium,dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline,diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine,diclomezine-sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl,dicrotophos, dicyclanil, dicyclonon, dieldrin, dienochlor, diethamquat,diethamquat dichloride, diethatyl, diethatyl-ethyl, diethofencarb,dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum,difenoconazole, difenopenten, difenopenten-ethyl, difenoxuron,difenzoquat, difenzoquat metilsulfate, difethialone, diflovidazin,diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium,diflumetorim, dikegulac, dikegulac-sodium, dilor, dimatif, dimefluthrin,dimefox, dimefuron, dimepiperate, dimetachlone, dimetan, dimethacarb,dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin,dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate,dimethyl phthalate, dimethylvinphos, dimetilan, dimexano, dimidazon,dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, diniconazole,diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6,dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinosebacetate, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium,dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb acetate,dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion,diphacinone, diphacinone-sodium, diphenamid, diphenyl sulfone,diphenylamine, dipropalin, dipropetryn, dipyrithione, diquat, diquatdibromide, disparlure, disul, disulfiram, disulfoton, disul-sodium,ditalimfos, dithianon, dithicrofos, dithioether, dithiopyr, diuron,d-limonene, DMPA, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium,dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicinhydrochloride, dodicin-sodium, dodine, dofenapyn, dominicalure,doramectin, drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone,edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate,EMPC, empenthrin, endosulfan, endothal, endothal-diammonium,endothal-dipotassium, endothal-disodium, endothion, endrin,enestroburin, EPN, epocholeone, epofenonane, epoxiconazole,eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan,esdépalléthrine, esfenvalerate, esprocarb, etacelasil, etaconazole,etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron,ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron,ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol,ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen,ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethylformate, ethyl α-naphthaleneacetate, ethyl-DDD, ethylene, ethylenedibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercurybromide, ethylmercury chloride, ethylmercury phosphate, etinofen,etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos,eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos,fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazole,fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos,fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan,fenitrothion, fenjuntong, fenobucarb, fenoprop, fenoprop-3-butoxypropyl,fenoprop-butometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoctyl,fenoprop-methyl, fenoprop-potassium, fenothiocarb, fenoxacrim,fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P,fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb, fenpiclonil,fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine,fenpyroximate, fenridazon, fenridazon-potassium, fenridazon-propyl,fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop-ethyl,fenthion, fenthion-ethyl, fentin, fentin acetate, fentin chloride,fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron TCA,fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil, flamprop,flamprop-isopropyl, flamprop-M, flamprop-methyl, flamprop-M-isopropyl,flamprop-M-methyl, flazasulfuron, flocoumafen, flometoquin, flonicamid,florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl,fluazifop-P, fluazifop-P-butyl, fluazinam, fluazolate, fluazuron,flubendiamide, flubenzimine, flucarbazone, flucarbazone-sodium,flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate,fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim,flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl,flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin,flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph,fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamid,fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl,fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole,fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate,flupropanate-sodium, flupyradifurone, flupyrsulfuron,flupyrsulfuron-methyl, flupyrsulfuron-methyl-sodium, fluquinconazole,flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone,flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl,flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide,fluthiacet, fluthiacet-methyl, flutianil, flutolanil, flutriafol,fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen,fomesafen-sodium, fonofos, foramsulfuron, forchlorfenuron, formaldehyde,formetanate, formetanate hydrochloride, formothion, formparanate,formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl,fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan,frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling,fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr,furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin,furfural, furilazole, furmecyclox, furophanate, furyloxyfen,gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid, gibberellins,gliftor, glufosinate, glufosinate-ammonium, glufosinate-P,glufosinate-P-ammonium, glufosinate-P-sodium, glyodin, glyoxime,glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium,glyphosate-isopropylammonium, glyphosate-monoammonium,glyphosate-potassium, glyphosate-sesquisodium, glyphosate-trimesium,glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatineacetates, halacrinate, halfenprox, halofenozide, halosafen,halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop,haloxyfop-etotyl, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-etotyl,haloxyfop-P-methyl, haloxyfop-sodium, HCH, hemel, hempa, HEOD,heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone,hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole,hexaflumuron, hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos,hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo,hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanide,hydroprene, hymexazol, hyquincarb, IAA, IBA, icaridin, imazalil,imazalil nitrate, imazalil sulfate, imazamethabenz,imazamethabenz-methyl, imazamox, imazamox-ammonium, imazapic,imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin,imazaquin-ammonium, imazaquin-methyl, imazaquin-sodium, imazethapyr,imazethapyr-ammonium, imazosulfuron, imibenconazole, imicyafos,imidacloprid, imidaclothiz, iminoctadine, iminoctadine triacetate,iminoctadine trialbesilate, imiprothrin, inabenfide, indanofan,indaziflam, indoxacarb, inezin, iodobonil, iodocarb, iodomethane,iodosulfuron, iodosulfuron-methyl, iodosulfuron-methyl-sodium,iofensulfuron, iofensulfuron-sodium, ioxynil, ioxynil octanoate,ioxynil-lithium, ioxynil-sodium, ipazine, ipconazole, ipfencarbazone,iprobenfos, iprodione, iprovalicarb, iprymidam, ipsdienol, ipsenol,IPSP, isamidofos, isazofos, isobenzan, isocarbamid, isocarbophos,isocil, isodrin, isofenphos, isofenphos-methyl, isolan, isomethiozin,isonoruron, isopolinate, isoprocarb, isopropalin, isoprothiolane,isoproturon, isopyrazam, isopyrimol, isothioate, isotianil, isouron,isovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl,isoxaflutole, isoxapyrifop, isoxathion, ivermectin, izopamfos,japonilure, japothrins, jasmolin I, jasmolin II, jasmonic acid,jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan,jiecaoxi, jodfenphos, juvenile hormone I, juvenile hormone II, juvenilehormone III, kadethrin, karbutilate, karetazan, karetazan-potassium,kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox,ketospiradox-potassium, kinetin, kinoprene, kresoxim-methyl, kuicaoxi,lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil,lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure,looplure, lufenuron, lvdingjunzhi, lvxiancaolin, lythidathion, MAA,malathion, maleic hydrazide, malonoben, maltodextrin, MAMA, mancopper,mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA,MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium,MCPA-diolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl,MCPA-methyl, MCPA-olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl,MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil,mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl,mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl,mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P-2-ethylhexyl,mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoprop-potassium,mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform,medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr,mefenpyr-diethyl, mefluidide, mefluidide-diolamine,mefluidide-potassium, megatomoic acid, menazon, mepanipyrim,meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride,mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride,mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron,mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone,metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop,metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron,metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron,methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole,methfuroxam, methidathion, methiobencarb, methiocarb,methiopyrisulfuron, methiotepa, methiozolin, methiuron, methocrotophos,methometon, methomyl, methoprene, methoprotryne, methoquin-butyl,methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methylapholate, methyl bromide, methyl eugenol, methyl iodide, methylisothiocyanate, methylacetophos, methylchloroform, methyldymron,methylene chloride, methylmercury benzoate, methylmercury dicyandiamide,methylmercury pentachlorophenoxide, methylneodecanamide, metiram,metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb,metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone,metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos,mexacarbate, mieshuan, milbemectin, milbemycin oxime, milneb, mipafox,mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron,monochloroacetic acid, monocrotophos, monolinuron, monosulfuron,monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquatdichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid,moxidectin, MSMA, muscalure, myclobutanil, myclozolin,N-(ethylmercury)-p-toluenesulphonanilide, nabam, naftalofos, naled,naphthalene, naphthaleneacetamide, naphthalic anhydride, naphthoxyaceticacids, naproanilide, napropamide, naptalam, naptalam-sodium, natamycin,neburon, niclosamide, niclosamide-olamine, nicosulfuron, nicotine,nifluridide, nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin,nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothal-isopropyl,norbormide, norflurazon, nomicotine, noruron, novaluron, noviflumuron,nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace,omethoate, orbencarb, orfralure, ortho-dichlorobenzene, orthosulfamuron,oryctalure, orysastrobin, oryzalin, osthol, ostramone, oxabetrinil,oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl, oxapyrazon,oxapyrazon-dimolamine, oxapyrazon-sodium, oxasulfuron, oxaziclomefone,oxine-copper, oxolinic acid, oxpoconazole, oxpoconazole fumarate,oxycarboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyfluorfen,oxymatrine, oxytetracycline, oxytetracycline hydrochloride,paclobutrazol, paichongding, para-dichlorobenzene, parafluron, paraquat,paraquat dichloride, paraquat dimetilsulfate, parathion,parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid,penconazole, pencycuron, pendimethalin, penflufen, penfluron,penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin,pentoxazone, perfluidone, permethrin, pethoxamid, phenamacril, phenazineoxide, phenisopham, phenkapton, phenmedipham, phenmedipham-ethyl,phenobenzuron, phenothrin, phenproxide, phenthoate, phenylmercuriurea,phenylmercury acetate, phenylmercury chloride, phenylmercury derivativeof pyrocatechol, phenylmercury nitrate, phenylmercury salicylate,phorate, phosacetim, phosalone, phosdiphen, phosfolan, phosfolan-methyl,phosglycin, phosmet, phosnichlor, phosphamidon, phosphine, phosphocarb,phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram,picloram-2-ethylhexyl, picloram-isoctyl, picloram-methyl,picloram-olamine, picloram-potassium, picloram-triethylammonium,picloram-tris(2-hydroxypropyl)ammonium, picolinafen, picoxystrobin,pindone, pindone-sodium, pinoxaden, piperalin, piperonyl butoxide,piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide,piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl,pirimiphos-methyl, plifenate, polycarbamate, polyoxins, polyoxorim,polyoxorim-zinc, polythialan, potassium arsenite, potassium azide,potassium cyanate, potassium gibberellate, potassium naphthenate,potassium polysulfide, potassium thiocyanate, potassiumα-naphthaleneacetate, pp′-DDT, prallethrin, precocene I, precocene II,precocene III, pretilachlor, primidophos, primisulfuron,primisulfuron-methyl, probenazole, prochloraz, prochloraz-manganese,proclonol, procyazine, procymidone, prodiamine, profenofos, profluazol,profluralin, profluthrin, profoxydim, proglinazine, proglinazine-ethyl,prohexadione, prohexadione-calcium, prohydrojasmon, promacyl, promecarb,prometon, prometryn, promurit, propachlor, propamidine, propamidinedihydrochloride, propamocarb, propamocarb hydrochloride, propanil,propaphos, propaquizafop, propargite, proparthrin, propazine,propetamphos, propham, propiconazole, propineb, propisochlor, propoxur,propoxycarbazone, propoxycarbazone-sodium, propyl isome,propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin,prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothiocarbhydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute,proxan, proxan-sodium, prynachlor, pydanon, pymetrozine, pyracarbolid,pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen-ethyl,pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole,pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl,pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II,pyrethrins, pyribambenz-isopropyl, pyribambenz-propyl, pyribencarb,pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl,pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon,pyriftalid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl,pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole,pyripropanol, pyriproxyfen, pyrithiobac, pyrithiobac-sodium, pyrolan,pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia,quinacetol, quinacetol sulfate, quinalphos, quinalphos-methyl,quinazamid, quinclorac, quinconazole, quinmerac, quinoclamine,quinonamid, quinothion, quinoxyfen, quintiofos, quintozene, quizalofop,quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl,quizalofop-P-tefuryl, quwenzhi, quyingding, rabenzazole, rafoxanide,rebemide, resmethrin, rhodethanil, rhodojaponin-III, ribavirin,rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong,salicylanilide, sanguinarine, santonin, schradan, scilliroside,sebuthylazine, secbumeton, sedaxane, selamectin, semiamitraz,semiamitraz chloride, sesamex, sesamolin, sethoxydim, shuangjiaancaolin,siduron, siglure, silafluofen, silatrane, silica gel, silthiofam,simazine, simeconazole, simeton, simetryn, sintofen, SMA, S-metolachlor,sodium arsenite, sodium azide, sodium chlorate, sodium fluoride, sodiumfluoroacetate, sodium hexafluorosilicate, sodium naphthenate, sodiumorthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide,sodium thiocyanate, sodium α-naphthaleneacetate, sophamide, spinetoram,spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine,streptomycin, streptomycin sesquisulfate, strychnine, sulcatol,sulcofuron, sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone,sulfiram, sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron,sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid,sulfuryl fluoride, sulglycapin, sulprofos, sultropen, swep,tau-fluvalinate, tavron, tazimcarb, TCA, TCA-ammonium, TCA-calcium,TCA-ethadyl, TCA-magnesium, TCA-sodium, TDE, tebuconazole, tebufenozide,tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron,tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin,tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim,terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton,terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane,tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin,tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate,thenylchlor, theta-cypermethrin, thiabendazole, thiacloprid,thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr,thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone,thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl,thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam,thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole-copper,thiodicarb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon,thionazin, thiophanate, thiophanate-methyl, thioquinox,thiosemicarbazide, thiosultap, thiosultap-diammonium,thiosultap-disodium, thiosultap-monosodium, thiotepa, thiram,thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid,tirpate, tolclofos-methyl, tolfenpyrad, tolylfluanid, tolylmercuryacetate, topramezone, tralkoxydim, tralocythrin, tralomethrin,tralopyril, transfluthrin, transpermethrin, tretamine, triacontanol,triadimefon, triadimenol, triafamone, tri-allate, triamiphos,triapenthenol, triarathene, triarimol, triasulfuron, triazamate,triazbutil, triaziflam, triazophos, triazoxide, tribenuron,tribenuron-methyl, tribufos, tributyltin oxide, tricamba, trichlamide,trichlorfon, trichlormetaphos-3, trichloronat, triclopyr,triclopyr-butotyl, triclopyr-ethyl, triclopyr-triethylammonium,tricyclazole, tridemorph, tridiphane, trietazine, trifenmorph,trifenofos, trifloxystrobin, trifloxysulfuron, trifloxysulfuron-sodium,triflumizole, triflumuron, trifluralin, triflusulfuron,triflusulfuron-methyl, trifop, trifop-methyl, trifopsime, triforine,trihydroxytriazine, trimedlure, trimethacarb, trimeturon, trinexapac,trinexapac-ethyl, triprene, tripropindan, triptolide, tritac,triticonazole, tritosulfuron, trunc-call, uniconazole, uniconazole-P,urbacide, uredepa, valerate, validamycin, valifenalate, valone,vamidothion, vangard, vaniliprole, vernolate, vinclozolin, warfarin,warfarin-potassium, warfarin-sodium, xiaochongliulin, xinjunan,xiwojunan, XMC, xylachlor, xylenols, xylylcarb, yishijing, zarilamid,zeatin, zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide,zinc thiazole, zineb, ziram, zolaprofos, zoxamide, zuomihuanglong,α-chlorohydrin, α-ecdysone, α-multistriatin, and α-naphthaleneaceticacid. For more information consult the “COMPENDIUM OF PESTICIDE COMMONNAMES” located at http://www.alanwood.net/pesticides/index.html. Alsoconsult “THE PESTICIDE MANUAL” 14th Edition, edited by C D S Tomlin,copyright 2006 by British Crop Production Council, or its prior or morerecent editions.

Biopesticides

Molecules of Formula One may also be used in combination (such as in acompositional mixture, or a simultaneous or sequential application) withone or more biopesticides. The term “biopesticide” is used for microbialbiological pest control agents that are applied in a similar manner tochemical pesticides. Commonly these are bacterial, but there are alsoexamples of fungal control agents, including Trichoderma spp. andAmpelomyces quisqualis (a control agent for grape powdery mildew).Bacillus subtilis are used to control plant pathogens. Weeds and rodentshave also been controlled with microbial agents. One well-knowninsecticide example is Bacillus thuringiensis, a bacterial disease ofLepidoptera, Coleoptera, and Diptera. Because it has little effect onother organisms, it is considered more environmentally friendly thansynthetic pesticides. Biological insecticides include products based on:

1. entomopathogenic fungi (e.g. Metarhizium anisopliae);

2. entomopathogenic nematodes (e.g. Steinemema feltiae); and

3. entomopathogenic viruses (e.g. Cydia pomonella granulovirus).

Other examples of entomopathogenic organisms include, but are notlimited to, baculoviruses, bacteria and other prokaryotic organisms,fungi, protozoa and Microsproridia. Biologically derived insecticidesinclude, but not limited to, rotenone, veratridine, as well as microbialtoxins; insect tolerant or resistant plant varieties; and organismsmodified by recombinant DNA technology to either produce insecticides orto convey an insect resistant property to the genetically modifiedorganism. In one embodiment, the molecules of Formula One may be usedwith one or more biopesticides in the area of seed treatments and soilamendments. The Manual of Biocontrol Agents gives a review of theavailable biological insecticide (and other biology-based control)products. Copping L. G. (ed.) (2004). The Manual of Biocontrol Agents(formerly the Biopesticide Manual) 3rd Edition. British Crop ProductionCouncil (BCPC), Farnham, Surrey UK.

Other Active Compounds

Molecules of Formula One may also be used in combination (such as in acompositional mixture, or a simultaneous or sequential application) withone or more of the following:

-   1.    3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-one;-   2.    3-(4′-chloro-2,4-dimethyl[1,1′-biphenyl]-3-yl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-one;-   3. 4-[[(6-chloro-3-pyridinyl)methyl]methylamino]-2(5H)-furanone;-   4.    4-[[(6-chloro-3-pyridinyl)methyl]cyclopropylamino]-2(5H)-furanone;-   5.    3-chloro-N2-[(1S)-1-methyl-2-(methylsulfonyl)ethyl]-N1-[2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-1,2-benzenedicarboxamide;-   6. 2-cyano-N-ethyl-4-fluoro-3-methoxy-benenesulfonamide;-   7. 2-cyano-N-ethyl-3-methoxy-benzenesulfonamide;-   8. 2-cyano-3-difluoromethoxy-N-ethyl-4-fluoro-benzenesulfonamide;-   9. 2-cyano-3-fluoromethoxy-N-ethyl-benzenesulfonamide;-   10. 2-cyano-6-fluoro-3-methoxy-N,N-dimethyl-benzenesulfonamide;-   11. 2-cyano-N-ethyl-6-fluoro-3-methoxy-N-methyl-benzenesulfonamide;-   12. 2-cyano-3-difluoromethoxy-N,N-dimethylbenzenesulfon-amide;-   13.    3-(difluoromethyl)-N-[2-(3,3-dimethylbutyl)phenyl]-1-methyl-1H-pyrazole-4-carboxamide;-   14.    N-ethyl-2,2-dimethylpropionamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)    hydrazone;-   15.    N-ethyl-2,2-dichloro-1-methylcyclopropane-carboxamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)    hydrazone nicotine;-   16.    O-{(E-)-[2-(4-chloro-phenyl)-2-cyano-1-(2-trifluoromethylphenyl)-vinyl]}S-methyl    thiocarbonate;-   17.    (E)-N1-[(2-chloro-1,3-thiazol-5-ylmethyl)]-N2-cyano-N1-methylacetamidine;-   18.    1-(6-chloropyridin-3-ylmethyl)-7-methyl-8-nitro-1,2,3,5,6,7-hexahydro-imidazo[1,2-a]pyridin-5-ol;-   19. 4-[4-chlorophenyl-(2-butylidine-hydrazono)methyl)]phenyl    mesylate; and-   20.    N-Ethyl-2,2-dichloro-1-methylcyclopropanecarboxamide-2-(2,6-dichloro-alpha,alpha,alpha-trifluoro-p-tolyl)hydrazone.

Synergistic Mixtures

Molecules of Formula One may be used with certain active compounds toform synergistic mixtures where the mode of action of such compoundscompared to the mode of action of the molecules of Formula One are thesame, similar, or different. Examples of modes of action include, butare not limited to: acetylcholinesterase inhibitor; sodium channelmodulator; chitin biosynthesis inhibitor; GABA and glutamate-gatedchloride channel antagonist; GABA and glutamate-gated chloride channelagonist; acetylcholine receptor agonist; acetylcholine receptorantagonist; MET I inhibitor; Mg-stimulated ATPase inhibitor; nicotinicacetylcholine receptor; Midgut membrane disrupter; oxidativephosphorylation disrupter, and ryanodine receptor (RyRs). Generally,weight ratios of the molecules of Formula One in a synergistic mixturewith another compound are from about 10:1 to about 1:10, in anotherembodiment from about 5:1 to about 1:5, and in another embodiment fromabout 3:1, and in another embodiment about 1:1.

Formulations

A pesticide is rarely suitable for application in its pure form. It isusually necessary to add other substances so that the pesticide can beused at the required concentration and in an appropriate form,permitting ease of application, handling, transportation, storage, andmaximum pesticide activity. Thus, pesticides are formulated into, forexample, baits, concentrated emulsions, dusts, emulsifiableconcentrates, fumigants, gels, granules, microencapsulations, seedtreatments, suspension concentrates, suspoemulsions, tablets, watersoluble liquids, water dispersible granules or dry flowables, wettablepowders, and ultra low volume solutions. For further information onformulation types see “Catalogue of Pesticide Formulation Types andInternational Coding System” Technical Monograph n°2, 5th Edition byCropLife International (2002).

Pesticides are applied most often as aqueous suspensions or emulsionsprepared from concentrated formulations of such pesticides. Suchwater-soluble, water-suspendable, or emulsifiable formulations areeither solids, usually known as wettable powders, or water dispersiblegranules, or liquids usually known as emulsifiable concentrates, oraqueous suspensions. Wettable powders, which may be compacted to formwater dispersible granules, comprise an intimate mixture of thepesticide, a carrier, and surfactants. The concentration of thepesticide is usually from about 10% to about 90% by weight. The carrieris usually selected from among the attapulgite clays, themontmorillonite clays, the diatomaceous earths, or the purifiedsilicates. Effective surfactants, comprising from about 0.5% to about10% of the wettable powder, are found among sulfonated lignins,condensed naphthalenesulfonates, naphthalenesulfonates,alkylbenzenesulfonates, alkyl sulfates, and non-ionic surfactants suchas ethylene oxide adducts of alkyl phenols.

Emulsifiable concentrates of pesticides comprise a convenientconcentration of a pesticide, such as from about 50 to about 500 gramsper liter of liquid dissolved in a carrier that is either a watermiscible solvent or a mixture of water-immiscible organic solvent andemulsifiers. Useful organic solvents include aromatics, especiallyxylenes and petroleum fractions, especially the high-boilingnaphthalenic and olefinic portions of petroleum such as heavy aromaticnaphtha. Other organic solvents may also be used, such as the terpenicsolvents including rosin derivatives, aliphatic ketones such ascyclohexanone, and complex alcohols such as 2-ethoxyethanol. Suitableemulsifiers for emulsifiable concentrates are selected from conventionalanionic and non-ionic surfactants.

Aqueous suspensions comprise suspensions of water-insoluble pesticidesdispersed in an aqueous carrier at a concentration in the range fromabout 5% to about 50% by weight. Suspensions are prepared by finelygrinding the pesticide and vigorously mixing it into a carrier comprisedof water and surfactants. Ingredients, such as inorganic salts andsynthetic or natural gums may also be added, to increase the density andviscosity of the aqueous carrier. It is often most effective to grindand mix the pesticide at the same time by preparing the aqueous mixtureand homogenizing it in an implement such as a sand mill, ball mill, orpiston-type homogenizer.

Pesticides may also be applied as granular compositions that areparticularly useful for applications to the soil. Granular compositionsusually contain from about 0.5% to about 10% by weight of the pesticide,dispersed in a carrier that comprises clay or a similar substance. Suchcompositions are usually prepared by dissolving the pesticide in asuitable solvent and applying it to a granular carrier which has beenpre-formed to the appropriate particle size, in the range of from about0.5 to about 3 mm Such compositions may also be formulated by making adough or paste of the carrier and compound and crushing and drying toobtain the desired granular particle size.

Dusts containing a pesticide are prepared by intimately mixing thepesticide in powdered form with a suitable dusty agricultural carrier,such as kaolin clay, ground volcanic rock, and the like. Dusts cansuitably contain from about 1% to about 10% of the pesticide. They canbe applied as a seed dressing or as a foliage application with a dustblower machine.

It is equally practical to apply a pesticide in the form of a solutionin an appropriate organic solvent, usually petroleum oil, such as thespray oils, which are widely used in agricultural chemistry.

Pesticides can also be applied in the form of an aerosol composition. Insuch compositions the pesticide is dissolved or dispersed in a carrier,which is a pressure-generating propellant mixture. The aerosolcomposition is packaged in a container from which the mixture isdispensed through an atomizing valve.

Pesticide baits are formed when the pesticide is mixed with food or anattractant or both. When the pests eat the bait they also consume thepesticide. Baits may take the form of granules, gels, flowable powders,liquids, or solids. They can be used in pest harborages.

Fumigants are pesticides that have a relatively high vapor pressure andhence can exist as a gas in sufficient concentrations to kill pests insoil or enclosed spaces. The toxicity of the fumigant is proportional toits concentration and the exposure time. They are characterized by agood capacity for diffusion and act by penetrating the pest'srespiratory system or being absorbed through the pest's cuticle.Fumigants are applied to control stored product pests under gas proofsheets, in gas sealed rooms or buildings or in special chambers.

Pesticides can be microencapsulated by suspending the pesticideparticles or droplets in plastic polymers of various types. By alteringthe chemistry of the polymer or by changing factors in the processing,microcapsules can be formed of various sizes, solubility, wallthicknesses, and degrees of penetrability. These factors govern thespeed with which the active ingredient within is released, which inturn, affects the residual performance, speed of action, and odor of theproduct.

Oil solution concentrates are made by dissolving pesticide in a solventthat will hold the pesticide in solution. Oil solutions of a pesticideusually provide faster knockdown and kill of pests than otherformulations due to the solvents themselves having pesticidal action andthe dissolution of the waxy covering of the integument increasing thespeed of uptake of the pesticide. Other advantages of oil solutionsinclude better storage stability, better penetration of crevices, andbetter adhesion to greasy surfaces.

Another embodiment is an oil-in-water emulsion, wherein the emulsioncomprises oily globules which are each provided with a lamellar liquidcrystal coating and are dispersed in an aqueous phase, wherein each oilyglobule comprises at least one compound which is agriculturally active,and is individually coated with a monolamellar or oligolamellar layercomprising: (1) at least one non-ionic lipophilic surface-active agent,(2) at least one non-ionic hydrophilic surface-active agent and (3) atleast one ionic surface-active agent, wherein the globules having a meanparticle diameter of less than 800 nanometers. Further information onthe embodiment is disclosed in U.S. patent publication 20070027034published Feb. 1, 2007, having patent application Ser. No. 11/495,228.For ease of use, this embodiment will be referred to as “OIWE”.

For further information consult “Insect Pest Management” 2nd Edition byD. Dent, copyright CAB International (2000). Additionally, for moredetailed information consult “Handbook of Pest Control—The Behavior,Life History, and Control of Household Pests” by Arnold Mallis, 9thEdition, copyright 2004 by GIE Media Inc.

Other Formulation Components

Generally, when the molecules disclosed in Formula One are used in aformulation, such formulation can also contain other components. Thesecomponents include, but are not limited to, (this is a non-exhaustiveand non-mutually exclusive list) wetters, spreaders, stickers,penetrants, buffers, sequestering agents, drift reduction agents,compatibility agents, anti-foam agents, cleaning agents, andemulsifiers. A few components are described forthwith.

A wetting agent is a substance that when added to a liquid increases thespreading or penetration power of the liquid by reducing the interfacialtension between the liquid and the surface on which it is spreading.Wetting agents are used for two main functions in agrochemicalformulations: during processing and manufacture to increase the rate ofwetting of powders in water to make concentrates for soluble liquids orsuspension concentrates; and during mixing of a product with water in aspray tank to reduce the wetting time of wettable powders and to improvethe penetration of water into water-dispersible granules. Examples ofwetting agents used in wettable powder, suspension concentrate, andwater-dispersible granule formulations are: sodium lauryl sulfate;sodium dioctyl sulfosuccinate; alkyl phenol ethoxylates; and aliphaticalcohol ethoxylates.

A dispersing agent is a substance which adsorbs onto the surface ofparticles and helps to preserve the state of dispersion of the particlesand prevents them from reaggregating. Dispersing agents are added toagrochemical formulations to facilitate dispersion and suspension duringmanufacture, and to ensure the particles redisperse into water in aspray tank. They are widely used in wettable powders, suspensionconcentrates and water-dispersible granules. Surfactants that are usedas dispersing agents have the ability to adsorb strongly onto a particlesurface and provide a charged or steric barrier to reaggregation ofparticles. The most commonly used surfactants are anionic, non-ionic, ormixtures of the two types. For wettable powder formulations, the mostcommon dispersing agents are sodium lignosulfonates. For suspensionconcentrates, very good adsorption and stabilization are obtained usingpolyelectrolytes, such as sodium naphthalene sulfonate formaldehydecondensates. Tristyrylphenol ethoxylate phosphate esters are also used.Non-ionics such as alkylarylethylene oxide condensates and EO-PO blockcopolymers are sometimes combined with anionics as dispersing agents forsuspension concentrates. In recent years, new types of very highmolecular weight polymeric surfactants have been developed as dispersingagents. These have very long hydrophobic ‘backbones’ and a large numberof ethylene oxide chains forming the ‘teeth’ of a ‘comb’ surfactant.These high molecular weight polymers can give very good long-termstability to suspension concentrates because the hydrophobic backboneshave many anchoring points onto the particle surfaces. Examples ofdispersing agents used in agrochemical formulations are: sodiumlignosulfonates; sodium naphthalene sulfonate formaldehyde condensates;tristyrylphenol ethoxylate phosphate esters; aliphatic alcoholethoxylates; alkyl ethoxylates; EO-PO block copolymers; and graftcopolymers.

An emulsifying agent is a substance which stabilizes a suspension ofdroplets of one liquid phase in another liquid phase. Without theemulsifying agent the two liquids would separate into two immiscibleliquid phases. The most commonly used emulsifier blends containalkylphenol or aliphatic alcohol with twelve or more ethylene oxideunits and the oil-soluble calcium salt of dodecylbenzenesulfonic acid. Arange of hydrophile-lipophile balance (“HLB”) values from 8 to 18 willnormally provide good stable emulsions. Emulsion stability can sometimesbe improved by the addition of a small amount of an EO-PO blockcopolymer surfactant.

A solubilizing agent is a surfactant which will form micelles in waterat concentrations above the critical micelle concentration. The micellesare then able to dissolve or solubilize water-insoluble materials insidethe hydrophobic part of the micelle. The types of surfactants usuallyused for solubilization are non-ionics, sorbitan monooleates, sorbitanmonooleate ethoxylates, and methyl oleate esters.

Surfactants are sometimes used, either alone or with other additivessuch as mineral or vegetable oils as adjuvants to spray-tank mixes toimprove the biological performance of the pesticide on the target. Thetypes of surfactants used for bioenhancement depend generally on thenature and mode of action of the pesticide. However, they are oftennon-ionics such as: alkyl ethoxylates; linear aliphatic alcoholethoxylates; aliphatic amine ethoxylates.

A carrier or diluent in an agricultural formulation is a material addedto the pesticide to give a product of the required strength. Carriersare usually materials with high absorptive capacities, while diluentsare usually materials with low absorptive capacities. Carriers anddiluents are used in the formulation of dusts, wettable powders,granules and water-dispersible granules.

Organic solvents are used mainly in the formulation of emulsifiableconcentrates, oil-in-water emulsions, suspoemulsions, and ultra lowvolume formulations, and to a lesser extent, granular formulations.Sometimes mixtures of solvents are used. The first main groups ofsolvents are aliphatic paraffinic oils such as kerosene or refinedparaffins. The second main group (and the most common) comprises thearomatic solvents such as xylene and higher molecular weight fractionsof C9 and C10 aromatic solvents. Chlorinated hydrocarbons are useful ascosolvents to prevent crystallization of pesticides when the formulationis emulsified into water. Alcohols are sometimes used as cosolvents toincrease solvent power. Other solvents may include vegetable oils, seedoils, and esters of vegetable and seed oils.

Thickeners or gelling agents are used mainly in the formulation ofsuspension concentrates, emulsions and suspoemulsions to modify therheology or flow properties of the liquid and to prevent separation andsettling of the dispersed particles or droplets. Thickening, gelling,and anti-settling agents generally fall into two categories, namelywater-insoluble particulates and water-soluble polymers. It is possibleto produce suspension concentrate formulations using clays and silicas.Examples of these types of materials, include, but are not limited to,montmorillonite, bentonite, magnesium aluminum silicate, andattapulgite. Water-soluble polysaccharides have been used asthickening-gelling agents for many years. The types of polysaccharidesmost commonly used are natural extracts of seeds and seaweeds or aresynthetic derivatives of cellulose. Examples of these types of materialsinclude, but are not limited to, guar gum; locust bean gum; carrageenam;alginates; methyl cellulose; sodium carboxymethyl cellulose (SCMC);hydroxyethyl cellulose (HEC). Other types of anti-settling agents arebased on modified starches, polyacrylates, polyvinyl alcohol andpolyethylene oxide. Another good anti-settling agent is xanthan gum.

Microorganisms can cause spoilage of formulated products. Thereforepreservation agents are used to eliminate or reduce their effect.Examples of such agents include, but are not limited to: propionic acidand its sodium salt; sorbic acid and its sodium or potassium salts;benzoic acid and its sodium salt; p-hydroxybenzoic acid sodium salt;methyl p-hydroxybenzoate; and 1,2-benzisothiazolin-3-one (BIT).

The presence of surfactants often causes water-based formulations tofoam during mixing operations in production and in application through aspray tank. In order to reduce the tendency to foam, anti-foam agentsare often added either during the production stage or before fillinginto bottles. Generally, there are two types of anti-foam agents, namelysilicones and non-silicones. Silicones are usually aqueous emulsions ofdimethyl polysiloxane, while the non-silicone anti-foam agents arewater-insoluble oils, such as octanol and nonanol, or silica. In bothcases, the function of the anti-foam agent is to displace the surfactantfrom the air-water interface.

“Green” agents (e.g., adjuvants, surfactants, solvents) can reduce theoverall environmental footprint of crop protection formulations. Greenagents are biodegradable and generally derived from natural and/orsustainable sources, e.g. plant and animal sources. Specific examplesare: vegetable oils, seed oils, and esters thereof, also alkoxylatedalkyl polyglucosides.

For further information, see “Chemistry and Technology of AgrochemicalFormulations” edited by D. A. Knowles, copyright 1998 by Kluwer AcademicPublishers. Also see “Insecticides in Agriculture andEnvironment—Retrospects and Prospects” by A. S. Perry, I. Yamamoto, I.Ishaaya, and R. Perry, copyright 1998 by Springer-Verlag.

Pests

In general, the molecules of Formula One may be used to control pestse.g. beetles, earwigs, cockroaches, flies. aphids, scales, whiteflies,leafhoppers, ants, wasps, termites, moths, butterflies, lice,grasshoppers, locusts, crickets, fleas, thrips, bristletails, mites,ticks, nematodes, and symphylans.

In another embodiment, the molecules of Formula One may be used tocontrol pests in the Phyla Nematoda and/or Arthropoda.

In another embodiment, the molecules of Formula One may be used tocontrol pests in the Subphyla Chelicerata, Myriapoda, and/or Hexapoda.

In another embodiment, the molecules of Formula One may be used tocontrol pests in the Classes of Arachnida, Symphyla, and/or Insecta.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Anoplura. A non-exhaustive list of particulargenera includes, but is not limited to, Haematopinus spp., Hoplopleuraspp., Linognathus spp., Pediculus spp., and Polyplax spp. Anon-exhaustive list of particular species includes, but is not limitedto, Haematopinus asini, Haematopinus suis, Linognathus setosus,Linognathus ovillus, Pediculus humanus capitis, Pediculus humanushumanus, and Pthirus pubis.

In another embodiment, the molecules of Formula One may be used tocontrol pests in the Order Coleoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Acanthoscelides spp.,Agriotes spp., Anthonomus spp., Apion spp., Apogonia spp., Aulacophoraspp., Bruchus spp., Cerosterna spp., Cerotoma spp., Ceutorhynchus spp.,Chaetocnema spp., Colaspis spp., Ctenicera spp., Curculio spp.,Cyclocephala spp., Diabrotica spp., Hypera spp., Ips spp., Lyctus spp.,Megascelis spp., Meligethes spp., Otiorhynchus spp., Pantomorus spp.,Phyllophaga spp., Phyllotreta spp., Rhizotrogus spp., Rhynchites spp.,Rhynchophorus spp., Scolytus spp., Sphenophorus spp., Sitophilus spp.,and Tribolium spp. A non-exhaustive list of particular species includes,but is not limited to, Acanthoscelides obtectus, Agrilus planipennis,Anoplophora glabripennis, Anthonomus grandis, Ataenius spretulus,Atomaria linearis, Bothynoderes punctiventris, Bruchus pisorum,Callosobruchus maculatus, Carpophilus hemipterus, Cassida vittata,Cerotoma trifurcata, Ceutorhynchus assimilis, Ceutorhynchus napi,Conoderus scalaris, Conoderus stigmosus, Conotrachelus nenuphar, Cotinisnitida, Crioceris asparagi, Cryptolestes ferrugineus, Cryptolestespusillus, Cryptolestes turcicus, Cylindrocopturus adspersus, Deporausmarginatus, Dermestes lardarius, Dermestes maculatus, Epilachnavarivestis, Faustinus cubae, Hylobius pales, Hypera postica,Hypothenemus hampei, Lasioderma serricorne, Leptinotarsa decemlineata,Liogenys fuscus, Liogenys suturalis, Lissorhoptrus oryzophilus,Maecolaspis joliveti, Melanotus communis, Meligethes aeneus, Melolonthamelolontha, Oberea brevis, Oberea linearis, Oryctes rhinoceros,Oryzaephilus mercator, Oryzaephilus surinamensis, Oulema melanopus,Oulema oryzae, Phyllophaga cuyabana, Popillia japonica, Prostephanustruncatus, Rhyzopertha dominica, Sitona lineatus, Sitophilus granarius,Sitophilus oryzae, Sitophilus zeamais, Stegobium paniceum, Triboliumcastaneum, Tribolium confusum, Trogoderma variabile, and Zabrustenebrioides.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Dermaptera.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Blattaria. A non-exhaustive list ofparticular species includes, but is not limited to, Blattella germanica,Blatta orientalis, Parcoblatta pennsylvanica, Periplaneta americana,Periplaneta australasiae, Periplaneta brunnea, Periplaneta fuliginosa,Pycnoscelus surinamensis, and Supella longipalpa.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Diptera. A non-exhaustive list of particulargenera includes, but is not limited to, Aedes spp., Agromyza spp.,Anastrepha spp., Anopheles spp., Bactrocera spp., Ceratitis spp.,Chrysops spp., Cochliomyia spp., Contarinia spp., Culex spp., Dasineuraspp., Delia spp., Drosophila spp., Fannia spp., Hylemyia spp., Liriomyzaspp., Musca spp., Phorbia spp., Tabanus spp., and Tipula spp. Anon-exhaustive list of particular species includes, but is not limitedto, Agromyza frontella, Anastrepha suspensa, Anastrepha ludens,Anastrepha obliqa, Bactrocera cucurbitae, Bactrocera dorsalis,Bactrocera invadens, Bactrocera zonata, Ceratitis capitata, Dasineurabrassicae, Delia platura, Fannia canicularis, Fannia scalaris,Gasterophilus intestinalis, Gracillia perseae, Haematobia irritans,Hypoderma lineatum, Liriomyza brassicae, Melophagus ovinus, Muscaautumnalis, Musca domestica, Oestrus ovis, Oscinella frit, Pegomyabetae, Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, Rhagoletismendax, Sitodiplosis mosellana, and Stomoxys calcitrans.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Hemiptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Adelges spp.,Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastesspp., Chionaspis spp., Chrysomphalus spp., Coccus spp., Empoasca spp.,Lepidosaphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp.,Nephotettix spp., Nezara spp., Philaenus spp., Phytocoris spp.,Piezodorus spp., Planococcus spp., Pseudococcus spp., Rhopalosiphumspp., Saissetia spp., Therioaphis spp., Toumeyella spp., Toxoptera spp.,Trialeurodes spp., Triatoma spp. and Unaspis spp. A non-exhaustive listof particular species includes, but is not limited to, Acrosternumhilare, Acyrthosiphon pisum, Aleyrodes proletella, Aleurodicusdispersus, Aleurothrixus floccosus, Amrasca biguttula biguttula,Aonidiella aurantii, Aphis gossypii, Aphis glycines, Aphis pomi,Aulacorthum solani, Bemisia argentifolii, Bemisia tabaci, Blissusleucopterus, Brachycorynella asparagi, Brevennia rehi, Brevicorynebrassicae, Calocoris norvegicus, Ceroplastes rubens, Cimex hemipterus,Cimex lectularius, Dagbertus fasciatus, Dichelops furcatus, Diuraphisnoxia, Diaphorina citri, Dysaphis plantaginea, Dysdercus suturellus,Edessa meditabunda, Eriosoma lanigerum, Eurygaster maura, Euschistusheros, Euschistus servus, Helopeltis antonii, Helopeltis theivora,Icerya purchasi, Idioscopus nitidulus, Laodelphax striatellus,Leptocorisa oratorius, Leptocorisa varicornis, Lygus hesperus,Maconellicoccus hirsutus, Macrosiphum euphorbiae, Macrosiphum granarium,Macrosiphum rosae, Macrosteles quadrilineatus, Mahanarva frimbiolata,Metopolophium dirhodum, Mictis longicornis, Myzus persicae, Nephotettixcinctipes, Neurocolpus longirostris, Nezara viridula, Nilaparvatalugens, Parlatoria pergandii, Parlatoria ziziphi, Peregrinus maidis,Phylloxera vitifoliae, Physokermes piceae, Phytocoris califomicus,Phytocoris relativus, Piezodorus guildinii, Poecilocapsus lineatus,Psallus vaccinicola, Pseudacysta perseae, Pseudococcus brevipes,Quadraspidiotus perniciosus, Rhopalosiphum maidis, Rhopalosiphum padi,Saissetia oleae, Scaptocoris castanea, Schizaphis graminum, Sitobionavenae, Sogatella furcifera, Trialeurodes vaporariorum, Trialeurodesabutiloneus, Unaspis yanonensis, and Zulia entrerriana.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Hymenoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Acromyrmex spp., Attaspp., Camponotus spp., Diprion spp., Formica spp., Monomorium spp.,Neodiprion spp., Pogonomyrmex spp., Polistes spp., Solenopsis spp.,Vespula spp., and Xylocopa spp. A non-exhaustive list of particularspecies includes, but is not limited to, Athalia rosae, Atta texana,Iridomyrmex humilis, Monomorium minimum, Monomorium pharaonis,Solenopsis invicta, Solenopsis geminata, Solenopsis molesta, Solenopsisrichtery, Solenopsis xyloni, and Tapinoma sessile.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Isoptera. A non-exhaustive list of particulargenera includes, but is not limited to, Coptotermes spp., Cornitermesspp., Cryptotermes spp., Heterotermes spp., Kalotermes spp.,Incisitermes spp., Macrotermes spp., Marginitermes spp., Microcerotermesspp., Procornitermes spp., Reticulitermes spp., Schedorhinotermes spp.,and Zootermopsis spp. A non-exhaustive list of particular speciesincludes, but is not limited to, Coptotermes curvignathus, Coptotermesfrenchi, Coptotermes formosanus, Heterotermes aureus, Microtermes obesi,Reticulitermes banyulensis, Reticulitermes grassei, Reticulitermesflavipes, Reticulitermes hageni, Reticulitermes hesperus, Reticulitermessantonensis, Reticulitermes speratus, Reticulitermes tibialis, andReticulitermes virginicus.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Lepidoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Adoxophyes spp.,Agrotis spp., Argyrotaenia spp., Cacoecia spp., Caloptilia spp., Chilospp., Chrysodeixis spp., Colias spp., Crambus spp., Diaphania spp.,Diatraea spp., Earias spp., Ephestia spp., Epimecis spp., Feltia spp.,Gortyna spp., Helicoverpa spp., Heliothis spp., Indarbela spp.,Lithocolletis spp., Loxagrotis spp., Malacosoma spp., Peridroma spp.,Phyllonorycter spp., Pseudaletia spp., Sesamia spp., Spodoptera spp.,Synanthedon spp., and Yponomeuta spp. A non-exhaustive list ofparticular species includes, but is not limited to, Achaea janata,Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, Amorbia cuneana,Amyelois transitella, Anacamptodes defectaria, Anarsia lineatella,Anomis sabulifera, Anticarsia gemmatalis, Archips argyrospila, Archipsrosana, Argyrotaenia citrana, Autographa gamma, Bonagota cranaodes,Borbo cinnara, Bucculatrix thurberiella, Capua reticulana, Carposinaniponensis, Chlumetia transversa, Choristoneura rosaceana,Cnaphalocrocis medinalis, Conopomorpha cramerella, Cossus cossus, Cydiacaryana, Cydia funebrana, Cydia molesta, Cydia nigricana, Cydiapomonella, Darna diducta, Diatraea saccharalis, Diatraea grandiosella,Earias insulana, Earias vittella, Ecdytolopha aurantianum, Elasmopalpuslignosellus, Ephestia cautella, Ephestia elutella, Ephestia kuehniella,Epinotia aporema, Epiphyas postvittana, Erionota thrax, Eupoeciliaambiguella, Euxoa auxiliaris, Grapholita molesta, Hedylepta indicata,Helicoverpa armigera, Helicoverpa zea, Heliothis virescens, Hellulaundalis, Keiferia lycopersicella, Leucinodes orbonalis, Leucopteracoffeella, Leucoptera malifoliella, Lobesia botrana, Loxagrotisalbicosta, Lymantria dispar, Lyonetia clerkella, Mahasena corbetti,Mamestra brassicae, Maruca testulalis, Metisa plana, Mythimna unipuncta,Neoleucinodes elegantalis, Nymphula depunctalis, Operophtera brumata,Ostrinia nubilalis, Oxydia vesulia, Pandemis cerasana, Pandemisheparana, Papilio demodocus, Pectinophora gossypiella, Peridroma saucia,Perileucoptera coffeella, Phthorimaea operculella, Phyllocnistiscitrella, Pieris rapae, Plathypena scabra, Plodia interpunctella,Plutella xylostella, Polychrosis viteana, Prays endocarpa, Prays oleae,Pseudaletia unipuncta, Pseudoplusia includens, Rachiplusia nu,Scirpophaga incertulas, Sesamia inferens, Sesamia nonagrioides, Setoranitens, Sitotroga cerealella, Sparganothis pilleriana, Spodopteraexigua, Spodoptera frugiperda, Spodoptera eridania, Thecla basilides,Tineola bisselliella, Trichoplusia ni, Tuta absoluta, Zeuzera coffeae,and Zeuzera pyrina.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Mallophaga. A non-exhaustive list ofparticular genera includes, but is not limited to, Anaticola spp.,Bovicola spp., Chelopistes spp., Goniodes spp., Menacanthus spp., andTrichodectes spp. A non-exhaustive list of particular species includes,but is not limited to, Bovicola bovis, Bovicola caprae, Bovicola ovis,Chelopistes meleagridis, Goniodes dissimilis, Goniodes gigas,Menacanthus stramineus, Menopon gallinae, and Trichodectes canis.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Orthoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Melanoplus spp., andPterophylla spp. A non-exhaustive list of particular species includes,but is not limited to, Anabrus simplex, Gryllotalpa africana,Gryllotalpa australis, Gryllotalpa brachyptera, Gryllotalpa hexadactyla,Locusta migratoria, Microcentrum retinerve, Schistocerca gregaria, andScudderia furcata.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Siphonaptera. A non-exhaustive list ofparticular species includes, but is not limited to, Ceratophyllusgallinae, Ceratophyllus niger, Ctenocephalides canis, Ctenocephalidesfelis, and Pulex irritans.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Thysanoptera. A non-exhaustive list ofparticular genera includes, but is not limited to, Caliothrips spp.,Frankliniella spp., Scirtothrips spp., and Thrips spp. A non-exhaustivelist of particular sp. includes, but is not limited to, Frankliniellafusca, Frankliniella occidentalis, Frankliniella schultzei,Frankliniella williamsi, Heliothrips haemorrhoidalis, Rhipiphorothripscruentatus, Scirtothrips citri, Scirtothrips dorsalis, and Taeniothripsrhopalantennalis, Thrips hawaiiensis, Thrips nigropilosus, Thripsorientalis, Thrips tabaci.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Thysanura. A non-exhaustive list ofparticular genera includes, but is not limited to, Lepisma spp. andThermobia spp.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Order Acarina. A non-exhaustive list of particulargenera includes, but is not limited to, Acarus spp., Aculops spp.,Boophilus spp., Demodex spp., Dermacentor spp., Epitrimerus spp.,Eriophyes spp., Ixodes spp., Oligonychus spp., Panonychus spp.,Rhizoglyphus spp., and Tetranychus spp. A non-exhaustive list ofparticular species includes, but is not limited to, Acarapis woodi,Acarus siro, Aceria mangiferae, Aculops lycopersici, Aculus pelekassi,Aculus schlechtendali, Amblyomma americanum, Brevipalpus obovatus,Brevipalpus phoenicis, Dermacentor variabilis, Dermatophagoidespteronyssinus, Eotetranychus carpini, Notoedres cati, Oligonychuscoffeae, Oligonychus ilicis, Panonychus citri, Panonychus ulmi,Phyllocoptruta oleivora, Polyphagotarsonemus latus, Rhipicephalussanguineus, Sarcoptes scabiei, Tegolophus perseaflorae, Tetranychusurticae, and Varroa destructor.

In another embodiment, the molecules of Formula One may be used tocontrol pest of the Order Symphyla. A non-exhaustive list of particularsp. includes, but is not limited to, Scutigerella immaculata.

In another embodiment, the molecules of Formula One may be used tocontrol pests of the Phylum Nematoda. A non-exhaustive list ofparticular genera includes, but is not limited to, Aphelenchoides spp.,Belonolaimus spp., Criconemella spp., Ditylenchus spp., Heterodera spp.,Hirschmanniella spp., Hoplolaimus spp., Meloidogyne spp., Pratylenchusspp., and Radopholus spp. A non-exhaustive list of particular sp.includes, but is not limited to, Dirofilaria immitis, Heterodera zeae,Meloidogyne incognita, Meloidogyne javanica, Onchocerca volvulus,Radopholus similis, and Rotylenchulus reniformis.

For additional information consult “HANDBOOK OF PEST CONTROL—THEBEHAVIOR, LIFE HISTORY, AND CONTROL OF HOUSEHOLD PESTS” by ArnoldMallis, 9th Edition, copyright 2004 by GIE Media Inc.

Applications

Molecules of Formula One are generally used in amounts from about 0.01grams per hectare to about 5000 grams per hectare to provide control.Amounts from about 0.1 grams per hectare to about 500 grams per hectareare generally preferred, and amounts from about 1 gram per hectare toabout 50 grams per hectare are generally more preferred.

The area to which a molecule of Formula One is applied can be any areainhabited (or maybe inhabited, or traversed by) a pest, for example:where crops, trees, fruits, cereals, fodder species, vines, turf andornamental plants, are growing; where domesticated animals are residing;the interior or exterior surfaces of buildings (such as places wheregrains are stored), the materials of construction used in building (suchas impregnated wood), and the soil around buildings. Particular cropareas to use a molecule of Formula One include areas where apples, corn,sunflowers, cotton, soybeans, canola, wheat, rice, sorghum, barley,oats, potatoes, oranges, alfalfa, lettuce, strawberries, tomatoes,peppers, crucifers, pears, tobacco, almonds, sugar beets, beans andother valuable crops are growing or the seeds thereof are going to beplanted. It is also advantageous to use ammonium sulfate with a moleculeof Formula One when growing various plants.

Controlling pests generally means that pest populations, pest activity,or both, are reduced in an area. This can come about when: pestpopulations are repulsed from an area; when pests are incapacitated inor around an area; or pests are exterminated, in whole, or in part, inor around an area. Of course, a combination of these results can occur.Generally, pest populations, activity, or both are desirably reducedmore than fifty percent, preferably more than 90 percent. Generally, thearea is not in or on a human; consequently, the locus is generally anon-human area.

The molecules of Formula One may be used in mixtures, appliedsimultaneously or sequentially, alone or with other compounds to enhanceplant vigor (e.g. to grow a better root system, to better withstandstressful growing conditions). Such other compounds are, for example,compounds that modulate plant ethylene receptors, most notably1-methylcyclopropene (also known as 1-MCP). Furthermore, such moleculesmay be used during times when pest activity is low, such as before theplants that are growing begin to produce valuable agriculturalcommodities. Such times include the early planting season when pestpressure is usually low.

The molecules of Formula One can be applied to the foliar and fruitingportions of plants to control pests. The molecules will either come indirect contact with the pest, or the pest will consume the pesticidewhen eating leaf, fruit mass, or extracting sap, that contains thepesticide. The molecules of Formula One can also be applied to the soil,and when applied in this manner, root and stem feeding pests can becontrolled. The roots can absorb a molecule taking it up into the foliarportions of the plant to control above ground chewing and sap feedingpests.

Generally, with baits, the baits are placed in the ground where, forexample, termites can come into contact with, and/or be attracted to,the bait. Baits can also be applied to a surface of a building,(horizontal, vertical, or slant surface) where, for example, ants,termites, cockroaches, and flies, can come into contact with, and/or beattracted to, the bait. Baits can comprise a molecule of Formula One.

The molecules of Formula One can be encapsulated inside, or placed onthe surface of a capsule. The size of the capsules can range fromnanometer size (about 100-900 nanometers in diameter) to micrometer size(about 10-900 microns in diameter).

Because of the unique ability of the eggs of some pests to resistcertain pesticides, repeated applications of the molecules of FormulaOne may be desirable to control newly emerged larvae.

Systemic movement of pesticides in plants may be utilized to controlpests on one portion of the plant by applying (for example by sprayingan area) the molecules of Formula One to a different portion of theplant. For example, control of foliar-feeding insects can be achieved bydrip irrigation or furrow application, by treating the soil with forexample pre- or post-planting soil drench, or by treating the seeds of aplant before planting.

Seed treatment can be applied to all types of seeds, including thosefrom which plants genetically modified to express specialized traitswill germinate. Representative examples include those expressingproteins toxic to invertebrate pests, such as Bacillus thuringiensis orother insecticidal toxins, those expressing herbicide resistance, suchas “Roundup Ready” seed, or those with “stacked” foreign genesexpressing insecticidal toxins, herbicide resistance,nutrition-enhancement, drought resistance, or any other beneficialtraits. Furthermore, such seed treatments with the molecules of FormulaOne may further enhance the ability of a plant to better withstandstressful growing conditions. This results in a healthier, more vigorousplant, which can lead to higher yields at harvest time. Generally, about1 gram of the molecules of Formula One to about 500 grams per 100,000seeds is expected to provide good benefits, amounts from about 10 gramsto about 100 grams per 100,000 seeds is expected to provide betterbenefits, and amounts from about 25 grams to about 75 grams per 100,000seeds is expected to provide even better benefits.

It should be readily apparent that the molecules of Formula One may beused on, in, or around plants genetically modified to expressspecialized traits, such as Bacillus thuringiensis or other insecticidaltoxins, or those expressing herbicide resistance, or those with“stacked” foreign genes expressing insecticidal toxins, herbicideresistance, nutrition-enhancement, or any other beneficial traits.

The molecules of Formula One may be used for controlling endoparasitesand ectoparasites in the veterinary medicine sector or in the field ofnon-human animal keeping. The molecules of Formula One are applied, suchas by oral administration in the form of, for example, tablets,capsules, drinks, granules, by dermal application in the form of, forexample, dipping, spraying, pouring on, spotting on, and dusting, and byparenteral administration in the form of, for example, an injection.

The molecules of Formula One may also be employed advantageously inlivestock keeping, for example, cattle, sheep, pigs, chickens, andgeese. They may also be employed advantageously in pets such as, horses,dogs, and cats. Particular pests to control would be fleas and ticksthat are bothersome to such animals. Suitable formulations areadministered orally to the animals with the drinking water or feed. Thedosages and formulations that are suitable depend on the species.

The molecules of Formula One may also be used for controlling parasiticworms, especially of the intestine, in the animals listed above.

The molecules of Formula One may also be employed in therapeutic methodsfor human health care. Such methods include, but are limited to, oraladministration in the form of, for example, tablets, capsules, drinks,granules, and by dermal application.

Pests around the world have been migrating to new environments (for suchpest) and thereafter becoming a new invasive species in such newenvironment. The molecules of Formula One may also be used on such newinvasive species to control them in such new environment.

The molecules of Formula One may also be used in an area where plants,such as crops, are growing (e.g. pre-planting, planting, pre-harvesting)and where there are low levels (even no actual presence) of pests thatcan commercially damage such plants. The use of such molecules in sucharea is to benefit the plants being grown in the area. Such benefits,may include, but are not limited to, improving the health of a plant,improving the yield of a plant (e.g. increased biomass and/or increasedcontent of valuable ingredients), improving the vigor of a plant (e.g.improved plant growth and/or greener leaves), improving the quality of aplant (e.g. improved content or composition of certain ingredients), andimproving the tolerance to abiotic and/or biotic stress of the plant.

Before a pesticide can be used or sold commercially, such pesticideundergoes lengthy evaluation processes by various governmentalauthorities (local, regional, state, national, and international).Voluminous data requirements are specified by regulatory authorities andmust be addressed through data generation and submission by the productregistrant or by a third party on the product registrant's behalf, oftenusing a computer with a connection to the World Wide Web. Thesegovernmental authorities then review such data and if a determination ofsafety is concluded, provide the potential user or seller with productregistration approval. Thereafter, in that locality where the productregistration is granted and supported, such user or seller may use orsell such pesticide.

A molecule according to Formula One can be tested to determine itsefficacy against pests. Furthermore, mode of action studies can beconducted to determine if said molecule has a different mode of actionthan other pesticides. Thereafter, such acquired data can bedisseminated, such as by the internet, to third parties.

The headings in this document are for convenience only and must not beused to interpret any portion hereof.

TABLE SECTION % Control (or Mortality) Rating BAW & CEW Rating Table50-100 A More than 0-Less than 50 B Not Tested C No activity noticed inthis bioassay D GPA Rating Table 80-100 A More than 0-Less than 80 B NotTested C No activity noticed in this bioassay D

TABLE 1 Structures for Compounds Compound Number Structure AI34

AI36

AI37

AI38

AI39

AI40

AI41

AI44

AI45

AC1

AC2

AC3

AC4

AC5

AC6

AC7

AC8

AC9

AC10

AC11

AC12

AC13

AC14

AC15

AC16

AC17

AC18

AC19

AC20

AC21

AC22

AC23

AC24

AC25

AC26

AC27

AC28

AC29

AC30

AC31

AC32

AC33

AC34

AC35

AC36

AC37

AC38

AC39

AC40

AC41

AC42

AC43

AC44

AC45

AC46

AC47

AC48

AC49

AC50

AC51

AC52

AC53

AC54

AC57

AC58

AC59

AC60

AC61

AC62

AC63

AC64

AC65

AC66

AC67

AC68

AC69

AC70

AC71

AC72

AC75

AC76

AC77

AC78

AC79

AC80

AC81

AC82

AC83

AC84

AC85

AC86

AC87

AC89

AC90

AC91

AC92

AC93

AC94

AC95

AC96

AC97

AC98

AC99

AC100

AC101

AC102

AC103

AC104

AC105

AC106

AC107

AC108

AC109

AC110

AC111

AC112

AC113

AC114

AC115

AC116

AC117

AC118

BC1

BC2

BC3

BC4

BC5

BC6

BC7

BC8

BC9

BC10

BC11

BC12

BC13

BC14

CI4

CI5

CI8

CI9

CI34

CI35

CI36

CI37

CI38

CI39

CI40

CI41

CI49

CI50

CI51

CI52

CI53

CI54

CI55

CI56

CI57

CC1

CC2

CC3

CC4

CC5

CC6

CC7

CC8

CC9

CC10

CC11

CC12

CC13

CC14

CC15

CC16

CC17

CC18

CC19

CC20

CC21

CC22

CC23

CC24

CC25

CC26

CC27

CC28

CC29

CC30

CC31

CC32

CC33

CC34

CC35

CC36

CC37

CC38

CC39

CC40

CC41

CC42

CC43

CC44

CC45

CC46

CC47

CC48

CC49

CC50

CC51

CC52

CC53

CC54

DC1

DC2

DC3

DC4

DC5

DC6

DC7

DC8

DC9

DC10

DC11

DC12

DC13

DC14

DC15

DC16

DC17

DC18

DC19

DC20

DC21

DC22

DC23

DC24

DC25

DC26

DC27

DC28

DC29

DC30

DC31

DC32

DC33

DC34

DC35

DC36

DC37

DC38

DC39

DC40

DC41

DC42

DC43

DC44

DC45

DC46

DC47

DC48

DC49

DC50

DC51

DC52

DC53

DC54

DC55

DC56

DC57

DC58

DC59

DC60

DC61

DC62

DC63

DC64

DC65

DC66

DC67

DC68

DC69

DC70

TABLE 2 Analytical Data for Compounds in Table 1. Compound mp Number (°C.) ESIMS ¹H NMR (δ)¹ IR (cm⁻¹) AC1 156-161 386.09 7.83 (m, 2H), ([M −H]⁻) 7.68-7.63 (m, 5H), 6.93 (dd, J = 15.6, 8.0 Hz, 1H), 6.81 (d J =15.6 Hz, 1H,), 4.15 (m, 1H), 2.80 (s, 3H) AC2 110-112 374 7.80 (d, J =8.4 Hz, 2H), ([M + H]⁺) 7.48 (d, J = 8.0 Hz, 2H), 7.38 (m, 1H), 7.30 (s,2H), 6.65 (d, J = 16.0 Hz, 1H), 6.46 (dd, J = 16.0, 8.0 Hz, 1H), 4.15(m, 1H) AC3 162-166 402.24 7.42 (m, 4H), 7.37 (t, J = 1.8 Hz, ([M + H]⁺)1H), 7.28 (s, 2H), 6.63 (d, J = 16.0 Hz, 1H), 6.41 (dd, J = 16.0, 8.4Hz, 1H), 4.15 (m, 1H), 3.20 (s, 3H), 3.00 (s, 3H) AC4 122-126 454 7.79(d, J = 1.2 Hz, 2H), ([M − H]⁻) 7.48 (d, J = 8.4 Hz, 2H), 7.38 (t, J =1.8 Hz, 1H), 7.30 (s, 2H), 6.64 (d, J = 15.6 Hz, 1H), 6.40 (dd, J =15.6, 8.0 Hz, 1H), 6.30 (m, 1H), 4.15 (m, 3H) AC5 444.12 7.67 (s, 3H),7.64 (d, J = 8.0 Hz, ([M + H]⁺) 2H), 7.42 (d, J = 8.0 Hz, 2H), 6.91 (dd,J = 15.6, 8.0 Hz, 1H), 6.80 (d, J = 15.6 Hz, 1H), 4.80 (m, 1H), 3.60 (brs, 8H) AC6 468.40 7.40 (m, 2H), 7.26 (m, 1657, 1113, ([M − H]⁻) 3H),6.56 (d, J = 16.0 Hz, 804 1H), 6.48 (dd, J = 16.0, 8.0 Hz, 1H), 5.82 (brs, 1H), 4.08 (m, 3H), 2.52 (s, 3H) AC7 511.02 8.39 (s, 1H), 7.74 (m,3276, 1645, ([M − H]⁻) 1H), 7.39 (m, 3H), 1111, 801 7.24 (m, 4H), 6.58(d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 6.16 (br s, 1H),4.63 (m, 2H), 4.12 (m, 1H), 2.41 (s, 3H) AC8 454.11 7.39 (s, 1H), 7.22(m, 1748, 1112, ([M − H]⁻) 2H), 7.19 (m, 3H), 801 6.53 (d, J = 16.0 Hz,1H), 6.39-6.34 (dd, J = 16.0, 8.0 Hz, 1H), 4.22 (m, 1H), 3.95 (t, J =7.0 Hz, 2H), 2.62 (t, J = 8.0 Hz, 2H), 2.30 (s, 3H), 2.18 (m, 2H) AC9494.02 7.45 (t, J = 7.6 Hz, 1H), 3276, 1645, ([M − H]⁻) 7.36 (m, 2H),7.21 (m, 1112, 801 3H), 7.15 (m, 4H), 6.56 (d, J = 16.0 Hz, 1H), 6.38(dd, J = 16.0, 8.4 Hz, 1H), 6.08 (br s, 1H), 4.68 (d, J = 5.6 Hz, 2H),4.11 (m, 1H), 2.44 (s, 3H) A10 140-143 458.00 7.38 (t, J = 1.6 Hz, 1H),([M − H]⁻) 7.34 (d, J = 7.6 Hz, 1H), 7.27 (m, 2H), 7.24 (m, 2H), 6.57(d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 6.16 (m 1H), 5.44(m, 1H), 4.12 (m, 1H), 3.51 (m, 2H), 3.40 (m, 2H), 2.44 (s, 3H) AC11476.17 7.39-7.29 (m, 9H), 3287, 1644, ([M − H]⁻) 7.24 (m, 2H), 6.56 (d,J = 16.0 Hz, 1112, 801 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 5.99 (br s,1H), 4.63 (d, J = 6.0 Hz, 1H), 4.11 (m, 1H), 2.47 (s, 3H) AC12 479.308.63 (d, J = 4.4 Hz, 1H), 3293, 1653, ([M + H]⁺) 7.71 (m, 1H), 7.47 (d,J = 8.4 Hz, 1112, 800 1H), 7.37 (m, 2H), 7.32 (m, 2H), 7.23 (m, 2H),7.13 (m, 1H), 6.58 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz,1H), 4.75 (d, J = 4.8 Hz, 2H), 4.12 (m, 1H), 2.49 (s, 3H) AC13 75-78490.04 7.38 (m, 2H), 7.27 (m, ([M − H]⁻) 3H), 7.23 (br s, 1H), 6.58 (d,J = 16.0 Hz, 1H), 6.45 (m 1H), 6.42 (dd, J = 16.0, 8.4 Hz, 1H), 4.91 (m1H), 4.64 (m, 2H), 4.14 (m, 1H), 4.04 (m, 2H), 2.46 (s, 3H) AC14 480.998.63 (s, 2H), 7.76 (d, J = 8.0 Hz, 3293, 1645, ([M + 2H]⁺) 1H), 7.36 (m,1113, 800 3H), 7.22 (m, 1H), 7.13 (m, 2H), 6.57 (d, J = 16.0 Hz, 1H),6.39 (dd, J = 16.0, 8.0 Hz, 1H), 6.13 (br s, 1H), 4.66 (d, J = 5.6 Hz,2H), 4.11 (m, 1H), 2.46 (s, 3H) AC15 59-61 516.86 7.45 (s, 1H), 7.37 (m,3246, 1635, ([M − H]⁻) 1H), 7.34 (m, 1H), 1112, 801 7.26 (m, 3H), 7.22(m, 1H), 6.57 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H),6.18 (m, 1H), 4.71 (d, J = 6.4 Hz, 2H), 4.11 (m, 1H), 2.46 (s, 3H) AC16506.93 8.47 (m, 1H), 8.19 (s, 1657, 1113, ([M + H]⁺) 1H), 7.76 (m, 1H),801 7.47 (m, 2H), 7.37 (m, 1H), 7.28 (m, 2H), 7.24 (m, 1H), 7.21 (m,1H), 6.59 (d, J = 16.0 Hz, 1H), 6.39 (dd, J = 16.0, 8.4 Hz, 1H), 4.12(m, 1H), 2.48 (s, 3H), 1.88 (s, 6H) AC17 70-73 494.98 7.49 (m, 2H), 7.38(m, ([M − H]⁻) 1H), 7.29 (m, 4H), 7.08 (m, 3H), 6.91 (m, 1H), 6.61 (d, J= 16.0 Hz, 1H), 6.48 (m, 1H), 6.43 (dd, J = 16.0, 8.0 Hz, 1H), 4.13 (m,1H), 2.49 (s, 3H) AC18 155-158 480.44 8.73 (d, J = 4.8 Hz, 2H), ([M +H]⁺) 7.53 (d, J = 8.4 Hz, 1H), 7.37 (m, 1H), 7.27 (m, 4H), 7.23 (m, 1H),7.11 (m, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.41 (dd, J = 16.0, 8.0 Hz,1H), 4.90 (d, J = 4.8 Hz, 2H), 4.13 (m, 1H), 2.52 (s, 3H) AC19 55-57471.66 7.37 (m, 1H), 7.33 (d, J = 7.6 Hz, ([M + H]⁺) 1H), 7.27 (m, 2H),7.22 (m, 2H), 6.57 (d, J = 16.0 Hz, 1H), 6.39 (dd, J = 16.0, 8.0 Hz,1H), 6.10 (brs, 1H), 4.13 (m, 2H), 3.94 (m, 1H), 3.79 (m, 2H), 3.35 (m,1H), 2.45 (s, 3H), 2.14 (m, 1H), 1.71 (m, 2H), 1.65 (m, 1H). AC20 467.687.37 (m, 2H), 7.27 (m, 3437, 1664, ([M + H]⁺) 2H), 7.23 (m, 2H), 1265,1114, 6.57 (d, J = 16.0 Hz, 1H), 746 6.38 (m, 3H), 6.01 (m, 1H), 4.63(d, J = 5.6 Hz, 2H), 4.13 (m, 1H), 2.45 (s, 3H) AC21 61-64 528.78 8.44(s, 1H), 8.18 (s, ([M + H]⁺) 1H), 7.83 (br s, 1H), 7.38 (m, 2H), 7.27(m, 2H), 7.25 (m, 2H), 7.21 (m, 1H), 6.57 (d, J = 16.0 Hz, 1H), 6.40(dd, J = 16.0, 8.0 Hz, 1H), 5.01 (s, 2H), 4.11 (m, 1H), 2.43 (s, 3H)AC22 545.08 8.39 (s, 1H), 7.73 (m, 3270, 1642, ([M − H]⁻) 1H), 7.40 (s,1H), 1111, 809 7.35 (m, 2H), 7.22 (m, 3H), 6.57 (d, J = 16.0 Hz, 1H),6.38 (dd, J = 16.0, 7.6 Hz, 1H), 6.14 (br s, 1H), 4.62 (d, J = 6.0 Hz,2H), 4.13 (m, 1H), 2.45 (s, 3H) AC23 492.35 7.42 (s, 2H), 7.36 (m, 3273,1641, ([M − H]⁻) 1H), 7.24 (m, 2H), 1250, 1113, 6.59 (d, J = 16.0 Hz,1H), 807 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 6.20 (br s, 1H), 5.46 (m, 1H),4.15 (m, 1H), 3.52 (m, 2H), 3.41 (m, 2H), 2.45 (s, 3H) AC24 129-132526.98 7.40 (m, 2H), 7.27 (m, 3298, 1664, ([M + H]⁺) 2H), 7.25 (m, 2H),1113, 803 6.92 (br s, 2H), 6.60 (m, 1H), 6.48 (dd, J = 16.0, 8.0 Hz,1H), 4.19 (d, J = 5.2, 2H), 4.08 (m, 1H), 3.99 (m, 2H), 2.46 (s, 3H)AC25 542.24 7.41 (m, 3H), 7.27 (m, 3257, 1652, ([M − H]⁻) 2H), 6.58 (d,J = 15.6 Hz, 1316, 1109, 1H), 6.42 (m, 2H), 807 4.92 (m, 1H), 4.65 (m,2H), 4.14 (m, 1H), 4.09 (m, 2H), 2.46 (s, 3H) AC26 550.69 7.45 (s, 1H),7.40 (s, 3255, 1638, ([M − H]⁻) 2H), 7.34 (d, J = 8.0 Hz, 1113, 809 1H),7.22 (m, 2H), 6.54 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz,1H), 4.71 (d, J = 6.0 Hz, 2H), 4.11 (m, 1H), 2.46 (s, 3H) AC27 541.008.46 (d, J = 4.0 Hz, 1H), 1653, 1113, ([M − H]⁻) 8.20 (s, 1H), 7.76 (m,809 1H), 7.47 (m, 2H), 7.41 (s, 2H), 7.23 (m, 2H), 7.21 (m, 1H), 6.59(d, J = 16.0 Hz, 1H), 6.37 (dd, J = 16.0, 8.4 Hz, 1H), 4.11 (m, 1H),2.48 (s, 3H), 1.88 (s, 6H) AC28 65-67 564.84 8.40 (s, 1H), 7.74 (m,3267, 1650, ([M − H]⁻) 2H), 7.42 (m, 3H), 1112, 809 7.36 (m, 2H), 6.72(br s, 1H), 6.52 (d, J = 16.0 Hz, 1H), 6.43 (dd, J = 16.0, 8.0 Hz, 1H),4.66 (d, J = 6.4 Hz, 2H), 4.12 (m, 1H) AC29 75-78 511.78 7.71 (d, J =8.4 Hz, 1H), ([M − H]⁻) 7.42 (m, 3H), 7.35 (m, 1H), 6.75 (br s, 1H),6.56 (d, J = 16.0 Hz, 1H), 6.43 (dd, J = 16.0, 8.0 Hz, 1H), 5.49 (m,1H), 4.14 (m, 1H), 3.50 (m, 4H) AC30 110-113 543.72 7.42 (d, J = 8.4 Hz,1H), ([M − H]⁻) 7.44 (s, 1H), 7.40 (s, 1H), 7.38 (m, 1H), 7.06 (br s,1H), 6.58 (d, J = 15.6 Hz, 1H), 6.45 (dd, J = 15.6, 8.0 Hz, 1H), 4.93(m, 1H), 4.65 (m, 2H), 4.13 (m, 3H) AC31 68-70 610.73 8.42 (s, 1H), 7.76(m, ([M + H]⁺) 1H), 7.61 (m, 2H), 7.39 (m, 4H), 6.54-6.39 (m, 3H), 4.66(d, J = 6.0 Hz, 2H), 4.12 (m, 1H) AC32 78-80 555.89 7.61 (m, 2H), 7.40(m, ([M − H]⁻) 3H), 6.54 (m, 2H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 5.46(m, 1H), 4.14 (m, 1H), 3.50 (m, 4H) AC33 182-184 587.68 7.62 (s, 1H),7.58 (d, J = 8.0 Hz, ([M − H]⁻) 1H), 7.40 (m, 3H), 6.84 (br s, 1H), 6.55(d, J = 15.6 Hz, 1H), 6.45 (dd, J = 15.6, 7.6 Hz, 1H), 4.93 (m 1H), 4.65(m, 2H), 4.13 (m, 4H) AC34 151-153 545.83 7.67 (s, 1H), 7.61 (d, J = 6.0Hz, ([M − H]⁻) 1H), 7.53 (m, 1H), 7.41 (s, 2H), 6.64 (d, J = 16.0 Hz,1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 6.18 (br s, 1H), 5.44 (m, 1H),4.14 (m, 1H), 3.50 (m, 2H), 3.40 (m, 2H) AC35 100-102 577.71 7.70 (s,1H), 7.63 (m, 3257, 1655, ([M − H]⁻) 1H), 7.53 (d, J = 7.6 Hz, 1113, 8081H), 7.41 (s, 2H), 6.53 (d, J = 16.0 Hz, 1H), 6.49 (m, 2H), 4.93 (m,1H), 4.64 (m, 2H), 4.13 (m, 1H), 4.03 (m, 2H) AC36 81-83 600.83 8.40 (s,1H), 7.73 (m, ([M + H]⁺) 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.0Hz, 1H), 7.40 (s, 2H), 7.35 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 16.0 Hz,1H), 6.46 (dd, J = 16.0, 7.6 Hz, 1H), 6.14 (m, 1H), 4.63 (d, J = 6.0 Hz,2H), 4.14 (m, 1H) AC37 512.68 8.39 (s, 1H), 7.73 (m, 3268, 1644, ([M +H]⁺) 1H), 7.48 (m, 2H), 1109, 820 7.34 (d, J = 7.6 Hz, 1H), 7.24 (m,3H), 6.55 (d, J = 16.0 Hz, 1H), 6.41 (dd, J = 16.0, 7.6 Hz, 1H), 6.12(m, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.13 (m, 1H), 2.45 (s, 3H) AC38 79-80528.85 8.46 (m, 1H), 7.73 (m, ([M − H]⁻) 1H), 7.35 (m, 4H), 7.22 (m,2H), 6.56 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 4.62(d, J = 6.0 Hz, 2H), 4.10 (m, 1H), 2.45 (s, 3H) AC39 141-144 477.83 9.19(s, 1H), 8.79 (s, ([M − H]⁻) 2H), 7.37 (m, 2H), 7.23 (m, 2H), 7.21 (m,1H), 6.57 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 7.6 Hz 1H), 6.21 (m,1H), 4.65 (s, 2H), 4.11 (m, 1H), 2.46 (s, 3H) AC40 69-72 484.67 8.33 (t,J = 5.6 Hz, 1H), ([M + H]⁺) 8.61 (m, 1H), 7.68 (m, 3H), 7.48 (m, 2H),6.86 (dd, J = 15.6, 8.2 Hz 1H), 6.74 (d, J = 15.6 Hz, 1H), 4.44 (m, 1H),3.76 (d, J = 6.0 Hz, 2H), 2.54 (m, 1H), 2.67 (s, 3H), 0.59 (m, 2H), 0.54(m, 2H) AC41 196-199 515.00 8.66 (d, J = 7.6 Hz, ([M − H]⁻) 1H), 8.39(t, J = 5.6 Hz, 1H), 7.65 (s, 3H), 7.45 (m, 3H), 6.86 (dd, J = 15.6, 8.8Hz, 1H), 6.74 (d, J = 15.6 Hz, 1H), 5.01 (m, 1H), 4.99 (m, 1H), 3.78 (d,J = 6.0 Hz, 2H), 3.40 (m, 2H), 3.22 (m, 2H), 2.37 (m, 3H) AC42 79-82534.72 7.99 (d, J = 8.0 Hz, ([M + H]⁺) 1H), 7.89 (d, J = 8.0 Hz, 1H),7.51 (m, 2H), 7.44 (m, 2H), 7.27 (m, 4H), 6.71 (t, J = 5.2 Hz, 1H), 6.59(d, J = 16.0 Hz, 1H), 6.41 (dd, J = 16.0, 8.0 Hz, 1H), 5.05 (d, J = 1.6Hz, 2H), 4.12 (m, 1H), 2.52 (m, 3H) AC43 481.75 8.69 (s, 1H), 8.52 (s,1663, ([M + H]⁺) 2H), 7.45 (d, J = 7.6 Hz, 1608, 1168, 1H), 7.37 (d, J =2.0 Hz, 1114, 801 1H), 7.26 (m, 2H), 7.21 (m, 1H), 6.83 (s, 1H), 6.58(d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.4 Hz, 1H), 4.81 (d, J = 5.6Hz, 2H), 4.12 (t, J = 8.4 Hz 1H), 2.45 (s, 3H) AC44 528.01 8.44 (d, J =2.4 Hz, 1H), 1640, 1166, ([M + H]⁺) 7.69 (d, J = 2.4 Hz, 1112, 800 1H),7.37 (m, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 7.26 (m, 1H), 7.24 (m, 3H),6.57 (d, J = 16.0 Hz, 1H), 6.39 (dd, J = 16.0, 8.0 Hz, 1H), 5.96 (d, J =7.2 Hz, 1H), 5.32 (t, J = 7.2 Hz, 1H), 4.11 (t, J = 8.4 Hz, 1H), 2.41(s, 3H), 1.61 (d, J = 7.2 Hz, 3H) AC45 512.88 7.66 (s, 1H), 7.37 (d, J =6.8 Hz, 1657, 1167, ([M + H]⁺) 2H), 7.26 (m, 1106, 800 3H), 7.18 (m,1H), 7.11 (m, 2H), 6.99 (m, 1H), 6.57 (d, J = 15.6 Hz, 1H), 6.39 (dd, J= 15.6, 8.0 Hz, 1H), 4.11 (t, J = 8.4 Hz, 1H), 3.36 (s, 3H), 2.43 (s,3H) AC46 61-64 575.93 8.42 (d, J = 2.0 Hz, 1H), ([M + H]⁺) 7.76 (d, J =2.4 Hz, 1H), 7.61 (m, 2H), 7.39 (m, 3H), 7.26 (s, 2H), 6.54 (d, J = 16.0Hz, 1H), 6.42 (dd, J = 16.0, 7.6 Hz, 1H), 4.65 (d, J = 6.0 Hz, 2H), 4.14(m, 1H) AC47 525.89 10.02 (s, 1H), 9.87 (s, 3280, 1640 ([M − H]⁻) 1H),8.47 (t, J = 6.0 Hz, 1H), 7.66 (s, 3H), 7.44 (s, 1H), 7.40 (d, J = 3.6Hz, 2H), 6.86 (dd, J = 15.6, 9.2 Hz, 1H), 6.74 (d, J = 15.6 Hz, 1H),4.82 (t, J = 9.6 Hz, 2H), 3.88 (d, J = 6.0 Hz, 2H), 2.36 (s, 3H), 1.63(m, 1H), 0.76 (m, 4H) AC48 509.96 7.37 (m, 7H), 7.34 (m, 3275, 1642 ([M− H]⁻) 3H),, 6.57 (d, J = 16.0 Hz, 1H), 6.39 (dd, J = 16.0, 8.0 Hz, 1H),6.01 (m, 1H), 4.60 (d, J = 6.0 Hz, 2H), 4.13 (m, 1H), 2.46 (s, 3H) AC49518.85 8.39 (d, J = 2.0 Hz, 1H), 1658, 1112, ([M + H]⁺) 8.11 (m, 1H),7.71 (d, J = 2.4 Hz, 1025, 2219 1H), 7.41 (m, 3H), 7.17 (m, 3H), 6.59(d, J = 16.0 Hz, 1H), 6.47 (dd, J = 16.0, 8.0 Hz, 1H), 4.66 (d, J = 5.6Hz, 2H), 4.14 (m, 1H) AC50 481.88 8.72 (m, 1H), 7.67 (s, 1654, 1112,([M + H]⁺) 3H), 7.46 (s, 1H), 800, 3069 7.40 (m, 2H), 7.08 (s, 1H), 6.82(m, 2H), 6.55 (d, J = 7.6 Hz, 1H), 4.82 (m, 1H), 4.48 (s, 2H), 3.65 (s,3H), 2.38 (s, 3H) AC51 540.83 7.45 (d, J = 7.6 Hz, 1H), 1652, 1571,([M + H]⁺) 7.38 (m, 1H), 7.27 (m, 802, 1114, 2H), 7.22 (m, 2H), 29266.85 (m, 1H), 6.58 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz,1H), 4.33 (m, 2H), 4.14 (m, 3H), 3.18 (s, 3H), 2.48 (s, 3H) AC52 488.297.33 (m, 2H), 7.25 (m, 1635, 11134, ([M − H]⁻) 3H), 6.56 (d, J = 15.6Hz, 813, 2927 1H), 6.37 (dd, J = 15.6, 8.0 Hz, 1H), 5.61 (d, J = 8.0 Hz,1H), 4.21 (m, 1H), 4.01 (m, 1H), 4.08 (m, 2H), 3.56 (t, J = 10.0 Hz,2H), 2.48 (m, 2H), 2.08 (m, 2H), 1.5 (m, 3H) AC53 532.92 8.49 (d, J =2.0 Hz, 1H), 1651, 3027, ([M + H]⁺) 7.69 (d, J = 2.4 Hz, 1H), 815, 11137.43 (d, J = 8.0 Hz, 1H), 7.34 (m, 3H), 7.26 (m, 2H), 6.95 (m, 1H), 6.58(d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 4.72 (d, J = 5.2Hz, 2H), 4.09 (m, 1H), 2.47 (s, 3H) AC54 529.06 8.37 (d, J = 5.2 Hz,1H), 1654, 3434, ([M − H]⁻) 7.41 (d, J = 8.0 Hz, 1H), 814, 1112 7.36 (m,3H), 7.31 (m, 1H), 7.26 (m, 2H), 6.58 (d, J = 16.0 Hz, 1H), 6.40 (dd, J= 16.0, 7.6 Hz, 1H), 5.20 (t, J = 5.6 Hz, 1H), 4.63 (d, J = 6.0 Hz, 2H),4.13 (m, 1H), 2.18 (s, 3H) AC57 464.96 8.69 (t, J = 6.0 Hz, 1H), 3417,1658, ([M + H]⁺) 8.58 (t, J = 6.0 Hz, 1H), 1165, 817 7.92 (s, 1H), 7.87(d, J = 6.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H),7.0 (m, 1H), 6.76 (d, J = 15.6 Hz, 1H), 6.76 (dd, J = 15.6, 8.0 Hz, 1H),4.01 (m, J = 8.0 Hz, 1H), 3.71 (m, 2H), 3.49 (m, 2H) AC58 124.4-126.9599.76 7.62 (m, 2H), 7.40 (s, ([M + H]⁺) 2H), 7.37 (d, J = 1.6 Hz, 1H),6.61 (t, J = 4.8 Hz, 1H), 6.55 (d, J = 16.0 Hz, 1H), 6.41 (dd, J = 16.0,7.6 Hz, 1H), 4.16 (d, J = 6.0 Hz, 2H), 4.01 (m, 1H), 1.56 (s, 9H) AC5980-83 497.40 8.42 (d, J = 2.1 Hz, 1H), ([M − H]⁻) 8.29 (d, J = 7.5 Hz,1H), 7.51 (m, 2H), 7.39 (m, 1H), 7.36 (m, 4H), 7.28 (m, 1H), 6.61 (d, J= 15.9 Hz, 1H), 6.45 (dd, J = 15.9, 7.8 Hz 1H), 4.14 (t, J = 8.4 Hz,1H), 2.51 (s, 3H) AC60 515.09 8.52 (s, 1H), 8.39 (d, J = 1.8 Hz, 1668,1589, ([M + H]⁻) 2H), 7.70 (d, J = 2.1 Hz, 1167, 1113, 1H), 7.62 (s, 8021H), 7.43 (s, 1H), 7.35 (m, 3H), 6.62 (d, J = 16.2 Hz, 1H), 6.52 (dd, J= 16.2, 7.5 Hz, 1H), 4.62 (d, J = 6.3 Hz, 2H), 4.19 (m, 1H), 2.76 (s,3H) AC61 461.90 8.07 (t, J = 8.0 Hz, 1H), 1658, 1114, ([M − H]⁻) 7.39(t, J = 2.0 Hz, 1H), 801 7.28 (d, J = 1.2 Hz, 3H), 7.17 (d, J = 1.6 Hz,1H), 7.11 (m, 1H), 6.59 (d, J = 15.6 Hz, 1H), 6.47 (dd, J = 15.6, 7.6Hz, 1H), 5.49 (m, 1H), 4.14 (t, J = 8.4 Hz, 1H), 3.48 (m, 4H) AC62105-108 528.88 8.62 (t, J = 6.4 Hz, 1H), ([M − H]⁻) 8.46 (m, 1H), 7.73(m, 5H), 7.48 (d, J = 7.6 Hz, 1H), 7.03 (dd, J = 15.6, 9.2 Hz, 1H), 6.81(d, J = 15.6 Hz, 1H), 4.86 (m, 1H), 3.97 (m, 4H) AC63 77-80 594.67 8.43(s, 1H), 7.76 (d, J = 2.4 Hz, 3257, 1653 ([M + H]⁺) 1H), 7.60 (m, 2H),7.38 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 6.4 Hz, 3H), 6.54 (d, J = 16.0Hz, 1H), 6.46 (m, 1H), 6.41 (dd, J = 16.0 8.0 Hz, 1H), 4.65 (d, J = 6.0Hz, 2H), 4.15 (m, 1H) AC64 83-85 580.72 7.72 (d, J = 8.0 Hz, 1H), ([M −H]⁻) 7.44 (s, 1H), 7.40 (s, 2H), 7.36 (d, J = 6.8 Hz, 1H), 7.05 (t, J =5.2 Hz, 1H), 6.70 (t, J = 5.2 Hz, 1H), 6.57 (d, J = 15.6 Hz, 1H), 6.44(dd, J = 15.6, 8.0 Hz, 1H), 4.23 (d, J = 5.6 Hz, 2H), 4.15 (m, 1H), 4.01(m, 2H) AC65 534.72 8.39 (d, J = 2.0 Hz, 1658, 1113, ([M − H]⁻) 1H),8.12 (t, J = 8.4 Hz, 817, 2925 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.34 (m,3H), 7.26 (m, 1H), 7.11 (m, 2H), 6.59 (d, J = 16.0 Hz, 1H), 6.46 (dd, J= 16.0, 8.0 Hz, 1H), 4.66 (d, J = 5.2 Hz, 2H), 4.13 (m, 1H) AC66 73-75624.61 7.88 (s, 1H), 7.63 (d, J = 1.6 Hz, ([M − H]⁻) 1H), 7.57 (d, J =8.0 Hz, 1H), 7.40 (m, 2H), 6.80 (t, J = 5.6 Hz, 1H), 6.70 (t, J = 5.6Hz, 1H), 6.56 (d, J = 16.0 Hz, 1H), 6.44 (dd, J = 16.0, 8.0 Hz, 1H),4.22 (m, 2H), 4.12 (m, 1H), 4.01 (m, 2H) AC67 479.82 8.07 (t, J = 8.0Hz, 1H), 3272, 1644 ([M − H]⁻) 7.34 (d, J = 6.0 Hz, 2H), 7.28 (s, 1H),7.17 (s, 2H), 6.59 (d, J = 15.6 Hz, 1H), 6.46 (dd, J = 15.6, 8.0 Hz,1H), 5.49 (m, 1H),, 4.12 (m, 1H), 3.49 (m, 4H). AC68 90-93 546.80 8.6(t, J = 6.4 Hz, 1H), 3315, 1684 ([M − H]⁻) 8.45 (m, 1H), 7.86 (d, J =6.4 Hz, 2H), 7.75 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 12.0 Hz, 1H), 7.48(d, J = 8.0 Hz, 1H), 7.03 (dd, J = 15.6, 9.6 Hz, 1H), 6.80 (d, J = 15.6Hz, 1H), 4.88 (m, 1H), 3.96 (m, 4H) AC69 542.82 7.41 (d, J = 8.0 Hz,1H), 3294, 1685 ([M − H]⁻) 7.34 (d, J = 5.6 Hz, 2H), 7.26 (m, 1H), 7.23(m, 1H), 6.81 (s, 1H), 6.57 (d, J = 15.6 Hz, 1H), 6.55 (s, 1H), 6.39(dd, J = 15.6, 8.0 Hz, 1H), 4.18 (m, 2H), 4.13 (m, 1H), 3.97 (m, 2H),2.46 (s, 3H) AC70 176-178 545.23 8.38 (d, J = 2.4 Hz, 1H), ([M − H]⁻)8.22 (d, J = 6.8 Hz, 2H), 7.71 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 6.0 Hz,2H), 7.30 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 6.93 (d, J =1.2 Hz, 1H), 6.60 (d, J = 15.6 Hz, 1H), 6.43 (dd, J = 15.6, 7.6 Hz, 1H),4.66 (d, J = 6.0 Hz, 2H), 4.13 (m, 1H), 3.98 (s, 3H) AC71 492.20 8.24(d, J = 7.6 Hz, 1H), 1639, 3079, ([M − H]⁻) 8.15 (d, J = 8.4 Hz, 1H),858 7.35 (d, J = 6.0 Hz, 2H), 7.13 (d, J = 1.2 Hz, 1H), 6.92 (s, 1H),6.61 (d, J = 16.0 Hz, 1H), 6.43 (dd, J = 16.0, 7.6 Hz, 1H), 5.48 (m,1H), 4.13 (m, 1H), 4.03 (s, 3H), 3.48 (m, 4H) AC72 543.05 8.42 (d, J =2.4 Hz, 1H), 1642, 3246, ([M − H]⁻) 7.75 (d, J = 2.4 Hz, 1H), 814, 11137.34 (m, 4H), 7.20 (m, 2H), 6.60 (d, J = 16.0 Hz, 1H), 6.36 (dd, J =16.0, 8.0 Hz, 1H), 6.12 (t, J = 5.6 Hz, 1H), 4.62 (d, J = 6.0 Hz, 2H),4.20 (m, 1H), 2.82 (m, 2H), 1.45 (t, J = 5.6 Hz, 3H) AC75 644.78 8.72(s, 1H), 7.97 (d, J = 7.2 Hz, 3431, 1652, ([M + H]⁺) 1H), 7.70 (d, J =8.4 Hz, 1171, 809 1H), 7.61 (m, 2H), 7.40 (m, 2H), 6.55 (m, 2H), 6.42(dd, J = 16.0, 8.0 Hz, 1H), 4.76 (d, J = 6.0 Hz, 2H), 4.12 (m, 1H) AC76531.34 8.87 (t, J = 6.0 Hz, 1H), 3120, 1708, ([M + H]⁺) 8.34 (d, J = 2.1Hz, 1H), 1171 7.85 (d, J = 6.3 Hz, 3H), 7.48 (m, 4H), 6.57 (d, J = 15.6Hz, 1H), 6.45 (dd, J = 15.6, 9.0 Hz, 1H), 4.84 (m, 1H), 4.49 (d, J = 5.7Hz, 2H), 2.82 (m, 2H), 2.36 (t, J = 5.6 Hz, 3H) AC77 531.1 8.87 (t, J =6.0 Hz, 1H), 3444, 1648, ([M + H]⁺) 8.34 (d, J = 2.1 Hz, 1H), 1114, 8147.85 (d, J = 6.3 Hz, 3H), 7.48 (m, 4H), 6.57 (d, J = 15.6 Hz, 1H), 6.45(dd, J = 15.6, 8.0 Hz, 1H), 4.84 (m, 1H), 4.49 (d, J = 5.7 Hz, 2H), 2.36(s, 3H) AC78 561.06 8.59 (t, J = 6.4 Hz, 1H), 3432, 1631, ([M + H]⁺)8.47 (t, J = 5.6 Hz, 1H), 1161, 840 7.89 (s, 2H), 7.45 (m, 3H), 6.87 (m,1H), 6.75 (d, J = 15.6 Hz, 1H), 4.85 (t, J = 8.0 Hz 1H), 3.98 (m, 4H),2.58 (s, 3H) AC79 610.97 8.69 (t, J = 6.0 Hz, 1H), 3303, 1658, ([M +H]⁺) 8.58 (t, J = 6.0 Hz, 1H), 1166, 817 7.92 (s, 1H), 7.87 (d, J = 6.4Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.0 (m,1H), 6.76 (d, J = 15.6 Hz, 1H) 4.83 (t, J = 8.0 Hz, 1H), 3.98 (m, 4H)AC80 561.06 7.37 (m, 3H), 7.26 (m, 3412, 1624, ([M + H]⁺) 1H), 7.24 (m,1H), 1157, 825 6.59 (d, J = 15.6 Hz, 1H), 6.39 (dd, J = 15.6, 8.0 Hz,1H), 4.24 (m, 4H), 3.90 (m, 1H), 2.83 (m, 2H), 1.26 (m, 3H) AC81  9-92546.93 8.73 (d, J = 5.6 Hz, ([M − H]⁻) 1H), 8.45 (t, J = 6.0 Hz, 1H),7.76 (s, 3H), 7.45 (m, 3H), 6.86 (dd, J = 16.0, 9.2 Hz, 1H), 4.83 (m,1H), 4.56 (m, 2H), 4.51 (m, 1H), 4.10 (m, 2H), 3.85 (d, J = 6.0 Hz, 2H),2.50 (m, 3H) AC82 477.69 7.38 (d, J = 1.8 Hz, 1646, 1353, ([M + H]⁺)2H), 7.33 (s, 1H), 1196, 1112, 7.27 (s, 3H), 6.58 (d, J = 16.0 Hz, 8001H), 6.42 (d, J = 8.1 Hz, 1H), 6.36 (dd, J = 16.0, 7.8 Hz, 1H), 4.71 (m,1H), 4.23 (m, 3H), 3.26 (m, 2H), 2.45 (s, 3H) AC83 493.83 8.07 (t, J =8.4 Hz, 1H), 1527, 1113, ([M − H]⁻) 7.39 (t, J = 1.6 Hz, 1H), 801, 1167,7.31 (d, J = 1.2 Hz, 1H), 1321 7.26 (m, 2H), 7.23 (m, 1H), 7.19 (d, J =1.6 Hz, 1H), 6.60 (d, J = 16.8 Hz, 1H), 6.49 (dd, J = 16.8, 7.6 Hz, 1H),4.90 (m, 1H), 4.64 (m, 2H), 4.14 (m, 2H), 4.10 (m, 1H) AC84 511.75 8.07(t, J = 8.0 Hz, 1H), 1645, 1113, ([M − H]⁻) 7.34 (m, 3H), 7.19 (d, J =13.2 Hz, 804, 3030, 1H), 6.60 (d, 1245 J = 16.4 Hz, 1H), 6.48 (dd, J =16.4, 8.0 Hz, 1H), 4.88 (m, 1H), 4.62 (m, 2H), 4.12 (m, 3H) AC85 523.838.60 (d, J = 6.8 Hz, 1H), 1652, 3039, ([M − H]⁻) 8.15 (d, J = 8.4 Hz,1H), 802, 1114 7.35 (d, J = 6.0 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.94(s, 1H), 6.60 (d, J = 15.6 Hz, 1H), 6.44 (dd, J = 7.6, 7.6 Hz, 1H), 4.93(m, 1H), 4.62 (m, 2H), 4.13 (m, 6H) AC86 524.36 7.35 (d, J = 6.3 Hz,3H), 3333, 1651, ([M + H]⁺) 7.26 (m, 2H), 7.20 (m, 815 1H), 6.60 (d, J =15.9 Hz, 1H), 6.47 (dd, J = 15.9, 6.6 Hz, 1H), 4.86 (m, 1H), 4.65 (m,2H), 4.13 (m, 3H), 2.84 (q, 2.8 Hz, 2H), 1.26 (m, 3H) AC87 495.82 8.07(t, J = 8.0 Hz, 1H), 1623, 1114, ([M − H]⁻) 7.52 (m, 3H), 7.19 (d, J =13.2 Hz, 816 1H), 6.59 (d, J = 16.4 Hz, 1H), 6.47 (dd, J = 16.4, 8.0 Hz,1H), 4.69 (m, 1H), 4.23 (m, 3H), 3.29 (m, 2H) AC89 509.89 7.43 (m, 2H),7.27 (m, 1666, 1166, ([M + H]⁺) 2H), 7.23 (m, 2H), 1112, 800 6.58 (d, J= 16.0 Hz, 1H), 6.41 (dd, J = 16.0, 7.6 Hz, 1H), 4.79 (d, J = 5.6 Hz,2H), 4.14 (m, 1H), 2.48 (s, 3H), 2.18 (m, 1H), 1.16 (m, 4H) AC90 656.98.34 (m, 1H), 8.27 (m, ([M − H]⁻) 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.49(d, J = 8.0 Hz, 2H), 7.40 (s, 2H), 7.36 (dd, J = 8.2, 1.7 Hz, 1H), 6.53(d, J = 16.0 Hz, 1H), 6.38 (dd, J = 15.9, 7.9 Hz, 1H), 4.89 (d, J = 8.4Hz, 2H), 4.48 (d, J = 9.0 Hz, 2H), 4.11 (m, 1H) AC91 640.9 8.18 (t, J =5.0 Hz, 1H), ([M − H]⁻) 7.58 (d, J = 1.6 Hz, 1H), 7.47 (d, J = 8.0 Hz,1H), 7.40 (s, 2H), 7.34 (dd, J = 8.1, 1.6 Hz, 1H), 6.52 (m, 2H), 6.37(dd, J = 15.9, 7.9 Hz, 1H), 4.54 (d, J = 4.9 Hz, 2H), 4.12 (m, 1H), 3.99(qd, J = 8.9, 6.5 Hz, 2H) AC92 640.9 9.16 (d, J = 6.1 Hz, 1H), ([M −H]⁻) 7.65 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.41 (m, 3H),7.21 (t, J = 5.6 Hz, 1H), 6.55 (d, J = 15.9 Hz, 1H), 6.41 (dd, J = 15.9,7.8 Hz, 1H), 4.59 (d, J = 5.6 Hz, 2H), 4.45 (qd, J = 9.0, 6.0 Hz, 2H),4.12 (q, J = 7.2 Hz, 1H) AC93 485.5 7.52-7.41 (d, J = 8.2 Hz, ¹³C NMR(δ)³ ([M + H]⁺) 1H), 7.39-7.34 (m, 1H), 169.91, 7.24-7.17 (d, J = 1.8Hz, 169.84, 2H), 7.02-6.92 (m, 2H), 138.23, 6.90-6.83 (d, J = 11.4 Hz,137.41, 1H), 6.71 (br s, 1H), 136.84, 6.17 (br s, 1H), 134.79, 6.12-6.01(dd, J = 11.4, 10.3 Hz, 134.69, 1H), 4.44-4.38 (d, J = 4.2 Hz, 131.07,1H), 128.69, 4.35-4.27 (m, 1H), 4.10-3.99 (d, J = 5.1 Hz, 127.49, 2H),127.43, 2.78-2.67 (m, 1H), 2.44 (s, 3H), 126.72, 0.88-0.78 (m, 2H),126.61 (q, J = 212.10 Hz), 0.60-0.45 (m, 2H) 125.61, 123.76, 47.89 (q, J= 28.28 Hz), 43.46, 22.65, 19.97, 8.21 AC94 511.6 8.36-8.24 (d, J = 2.4Hz, 3262, 1607, ([M]⁻) 1H), 7.75-7.64 (m, 1247, 1164, 1H), 7.38-7.24 (m,1111 3H), 7.24-7.09 (d, J = 1.8 Hz, 2H), 6.99-6.90 (m, 2H), 6.89-6.74(d, J = 11.4 Hz, 1H), 6.63-6.43 (m, 1H), 6.14-5.98 (m, 1H), 4.69-4.51(d, J = 6.1 Hz, 2H), 4.37-4.20 (m, 1H), 2.46-2.31 (s, 3H) AC95 48-61626.9 7.58 (d, J = 7.9 Hz, 1H), ([M + H]⁺) 7.44-7.29 (m, 3H), 7.14 (dd,J = 7.9, 1.6 Hz, 1H), 6.86 (d, J = 11.4 Hz, 1H), 6.76 (t, J = 5.9 Hz,1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J = 5.5 Hz, 1H), 3.98(qd, J = 9.0, 6.5 Hz, 2H) AC96 619.6 8.83 (s, 1H), 8.06 (br, 1616, 1114([M + H]⁺) 1H), 7.90 (s, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.53 (m, 1H),6.94 (m, 1H), 6.77 (d, J = 15.3 Hz, 1H), 6.63 (d, J = 9.3 Hz, 1H), 4.84(m, 1H), 4.30 (d, J = 5.6 Hz, 2H), 2.99 (s, 6H) AC97 606.6 8.20 (d, J =2.1 Hz, 1644, 1113 ([M + H]⁺) 1H), 7.73 (d, J = 2.7 Hz, 1H), 7.60 (m,2H), 7.39 (s, 2H), 7.29 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.55 (d, J =15.9 Hz, 1H), 6.40 (m, 2H), 4.60 (d, J = 2.7 Hz, 2H), 4.13 (m, 1H), 3.95(s, 3H) AC98 577.87 9.04 (t, J = 6.0 Hz, 1H), 1663, 1168 ([M + H]⁺) 8.60(t, J = 6.6 Hz, 1H), 8.25 (s, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.87 (d, J= 6.3 Hz, 2H), 7.69 (d, J = 7.5 Hz, 1H), 7.15 (dd, J = 15.9, 9.3 Hz,1H), 6.89 (d, J = 15.9 Hz, 1H), 4.86 (m, 1H), 3.98 (m, 4H). AC99 574.818.69 (t, J = 6.0 Hz, 1H), 1650, 1164 ([M + H]⁺) 8.58 (t, J = 6.6 Hz,1H), 7.91 (s, 1H), 7.85 (m, 1H), 7.61 (m, 2H), 7.52 (m, 2H), 6.98 (dd, J= 15.3, 9.0 Hz, 1H), 6.76 (d, J = 15.3 Hz, 1H), 4.81 (m, 1H), 4.01 (m,4H) AC100 673.80 8.29 (s, 1H), 8.22 (d, J = 8.1 Hz, 3403, 1659 ([M +H]⁺) 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.72 (m, 1H), 7.65 (m, 2H), 7.40 (s,2H), 7.18 (br, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.43 (dd, J = 16.0, 7.6Hz, 1H), 5.02 (d, J = 1.2 Hz, 2H), 4.12 (m, 1H) AC101 636.83 7.56 (d, J= 9.0 Hz, 1637, 1113 ([M + H]⁺) 1H), 7.39 (d, J = 6.0 Hz, 2H), 7.26 (m,2H), 6.54 (d, J = 15.9 Hz, 1H), 6.37 (dd, J = 8.0, 15.9 Hz, 1H), 4.01(m, 1H), 3.84 (m, 2H), 3.33 (m, 2H), 3.04 (m, 2H), 2.84 (m, 3H), 2.62(m, 1H) AC102 592.84 7.60 (m, 2H), 7.32 (m, 1668, 1167 ([M + H]⁺) 1H),7.03 (d, J = 7.2 Hz, 2H), 6.74 (br, 1H), 6.62 (br, 1H), 6.56 (d, J =16.2 Hz, 1H), 6.41 (dd, J = 16.2, 7.8 Hz, 1H), 4.22 (d, J = 5.4 Hz, 2H),4.14 (m, 1H), 4.01 (m, 2H) AC103  99.2-105.0 612.7 8.40 (d, J = 8.0 Hz,1H), 1634, 1113, ([M + H]⁺) 7.92 (d, J = 5.2 Hz, 1H), 809 7.59 (d, J =8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 6.99 (dd, J = 16.0, 7.6 Hz, 1H),6.76 (d, J = 16.0 Hz, 1H), 4.84 (m, 1H), 4.23 (d, J = 13.2 Hz, 1H), 3.97(m, 1H), 3.79 (d, J = 13.6 Hz, 1H), 3.16 (t, J = 11.2 Hz, 1H), 2.77 (t,J = 11.2 Hz, 1H), 1.99 (s, 3H), 1.88 (m, 2H), 1.45 (m, 2H) AC104 680.977.60 (m, 2H), 7.40 (m 3437, ([M + H]⁺) 3H), 6.55 (d, J = 15.6 Hz, 1644,1H), 6.41 (dd, J = 15.6, 1113, 7.8 Hz, 1H), 807, 4.24 (m, 1H), 3.34 (m,2H), 511 2.90 (m, 1H), 2.24 (m, 2H), 1.52 (m, 2H), 1.34 (m, 4H) AC105609.9 7.59 (s, 1H), 7.55 (m, 3303, 1649, ([M + H]⁺) 1H), 7.50 (m, 1H),1115, 2242, 7.40 (m, 2H), 6.54 (d, J = 16.0 Hz, 809, 506 1H), 6.50 (J =16.0, 8.0 Hz, 1H), 4.14 (m, 2H), 3.08 (m, 4H), 2.67 (m, 2H), 2.12 (m,2H), 1.70 (m, 2H). AC106 584.95 7.59 (s, 1H), 7.51 (d, J = 8.4 Hz, 3417,([M + H]⁺) 1H), 7.40 (s, 1648, 2H), 7.36 (d, J = 6.8 Hz, 1112, 1H), 6.54(d, J = 16.0 Hz, 805, 555 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 6.03 (d,J = 8.0 Hz, 1H), 4.11 (m, 2H), 3.10 (m, 2H), 2.50 (m, 2H), 2.50 (s, 3H)(m, 2H), 1.94 (m, 2H) AC107 609.9 8.41 (d, J = 7.8 Hz, 1H), 3303, ([M +H]⁺) 7.90 (s, 2H), 7.62 (m, 1645, 2H), 7.51 (m, 1H), 1115, 6.92 (dd, J =15.9, 9.0 Hz, 2243, 1H), 6.77 (d, J = 15.9 Hz, 810, 1H), 4.81 (m, 1H),507 3.73 (s, 2H), 3.31 (m, 1H), 3.28 (m, 1H), 2.82 (t, J = 11.4 Hz, 2H),2.82 (m, 2H), 2.30 (m, 2H), 1.88 (m, 2H), 1.57 (m, 2H) AC108 626.9 7.60(m, 2H) 7.39 (s, 3420, ([M + H]⁺) 2H), 7.28 (m, 1H), 1649, 6.56 (d, J =15.6 Hz, 1H), 1113, 6.40 (dd, J = 15.6, 7.8 Hz, 809, 1H), 5.91 (m, 1H),554 4.65 (m, 2H), 4.10 (m, 1H), 4.07 (m, 2H), 3.59 (m, 1H), 2.74 (m,2H), 2.13 (m, 4H), 2.07 (m, 1H) AC109 614.6 7.56 (m, 2H), 7.39 (s, 1647,1113 ([M + H]⁺) 2H), 7.29 (s, 1H), 6.50 (d, J = 15.9 Hz, 1H), 6.41 (dd,J = 15.9, 8.0 Hz 1H), 4.09 (m, 1H), 3.88 (m, 2H), 3.49 (m, 2H), 2.92 (m,2H), 2.81 (m, 1H), 2.74 (m, 2H), 2.25 (m, 4H) AC110 572.6 11.20 (s, 1H),8.66 (br, 3412, 1690, ([M + H]⁺) 1H), 7.92 (m, 3H), 1114, 846, 7.62 (d,J = 8.0 Hz, 1H), 559 7.45 (d, J = 8.0 Hz, 1H), 6.77 (dd, J = 15.6, 9.2Hz, 1H), 6.77 (d, J = 15.6 Hz, 1H), 4.85 (m, 1H), 3.74 (d, J = 5.2 Hz,2H), 3.61 (s, 3H) AC111 582.79 8.63 (t, J = 6.0 Hz, 1H), 3419, 1659,([M + H]⁺) 8.04 (t, J = 6.0 Hz, 1H), 843, 557 7.92 (m, 3H), 7.62 (d, J =1.2 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.00 (dd, J = 15.6, 8.8 Hz, 1H),6.77 (d, J = 15.6 Hz, 1H), 5.19 (d, J = 1.6 Hz, 1H), 5.01 (d, J = 1.2Hz, 1H), 4.85 (m, 1H), 3.86 (d, J = 5.6 Hz, 2H), 3.75 (t, J = 5.6 Hz,2H) AC112 582.79 8.84 (br, 1H), 8.58 (m, 3399, 1662, ([M + H]⁺) 1H),8.30 (m, 1H), 1114, 807, 7.91 (s, 2H), 7.61 (d, J = 8.1 Hz, 582 1H),7.42 (d, J = 7.8 Hz, 1H), 7.00 (dd, J = 15.6, 9.3 Hz, 1H), 6.77 (d, J =15.6 Hz, 1H), 4.85 (m, 1H), 4.11 (d, J = 5.6 Hz, 1H), 3.73 (d, J = 5.6Hz, 1H), 3.04 (s, 6H) AC113 626.88 8.48 (t, J = 5.2 Hz, 1H), 3431, 1651,([M + H]⁺) 8.3 (s, 1H), 7.90 (s, 2H), 1113, 808, 7.79 (dd, J = 2.0, 2.0Hz 554 2H), 7.58 (d, J = 8.4 Hz, 1H) 7.46 (d, J = 7.6 Hz, 1H) 7.26 (d, J= 7.6 Hz, 1H), 6.98 (m, 1H), 6.75 (d, J = 15.6 Hz, 1H), 4.85 (m, 1H),3.49 (d, J = 6.4 Hz, 2H) 2.87 (t, J = 6.4 Hz, 2H) AC114 113.7-117.5570.7 8.77 (s, 1H), 8.58 (d, J = 7.2 Hz, ([M + H]⁺) 2H), 7.93 (d, J =7.2 Hz, 2H), 7.60 (dd, J = 1.2, 0.8 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H),6.99 (m, 1H), 6.77 (d, J = 16 Hz, 1H), 4.85 (m, 1H), 4.10 (m, 1H) 3.29(m, 2H), 3.05 (m, 2H), 2.0 (m, 2H), 1.76 (m, 2H) AC115 529.00 8.43 (s,1H), 7.79 (d, J = 8.0 Hz, 1589, 3459, ([M + H]⁺) 1H), 7.51 (m, 801, 11101H), 7.36 (d, J = 8.4 Hz, 3H), 7.21 (m, 3H), 6.55 (d, J = 15.6 Hz, 1H),6.36 (dd, J = 15.6, 8.0 Hz, 1H), 5.04 (d, J = 5.6 Hz, 2H), 4.10 (m, 1H),2.35 (s, 3H) AC116 614.87 7.99 (d, J = 8.4 Hz, 1H), 3424, 1657, ([M +H]⁺) 7.46 (d, J = 1.6 Hz, 1H), 1165 7.34 (d, J = 6.4 Hz, 2H), 7.28 (m,2H), 6.62 (m, 2H), 6.47 (dd, J = 16.0, 7.2 Hz, 1H), 4.23 (m, 2H), 4.12(m, 1H), 4.00 (m, 2H) AC117 525.42 8.39 (br, 1H), 7.85 (br, 3401, 1636,([M − H]⁻) 1H), 7.62 (m, 3H), 1113, 750 7.53 (d, J = 8.0 Hz, 1H), 7.46(s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.17 (m, 1H), 6.78 (dd, J = 16.0, 8.8Hz, 1H), 6.70 (m, 1H), 4.77 (m, 1H), 4.66 (s, 1H), 4.32 (s, 1H), 2.97(s, 3H), 2.16 (s, 3H) AC118 471.79 7.36 (d, J = 8.0 Hz, 2H), 3437, 1655,([M + H]⁺) 7.27 (m, 2H), 7.22 (m, 1262, 1105, 2H), 6.57 (d, J = 16.0 Hz,802 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 6.10 (br, 1H), 4.15 (m, 2H),3.89 (m, 1H), 3.80 (m, 2H), 3.35 (m, 1H), 2.46 (s, 3H), 2.06 (s, 1H),1.96 (m, 2H), 1.65 (m, 1H) BC1 492.17 7.39 (s, 2H), 3211, 1569, ([M +H]⁺) 7.25-7.18 (m, 3H), 6.58 (d, J = 16.0 Hz, 1113, 806 1H), 6.30 (dd, J= 16.0, 8.4 Hz, 1H), 5.91-5.70 (br, 2H), 4.05 (m, 1H), 3.05-2.80 (m,6H), 2.70 (m, 1H), 1.81 (m, 1H) BC2 506.4 8.80 (s, 1H), 8.20 (s, 2923,1542, ([M + H]⁺) 1H), 7.82 (m, 3H), 1033, 805 7.4 (s, 2H), 6.62 (d, J =16.0 Hz, 1H), 6.52 (dd, J = 16.0, 8.0 Hz, 1H), 4.18 (m, 1H), 3.38 (m,2H), 2.98 (m, 2H), 2.71 (m, 1H), 2.04 (m, 2H), 1.54 (s, 3H). BC3 518.047.40 (s, 2H), 3120, 1592, ([M − H]⁻) 7.33-7.22 (m, 3H), 6.61 (d, J =16.0 Hz, 1146, 895 1H), 6.34-6.28 (dd, J = 16.0, 8.0 Hz, 1H), 5.96-5.80(m, 3H), 5.22 (m, 4H), 4.01 (m, 2H), 2.84-2.99 (m, 2H), 2.71 (m, 1H),1.86 (m, 1H) BC4 529.02 7.39 (s, 2H), 3283, 1652, ([M + H]⁺) 7.25-7.20(m, 3H), 6.34 (d, J = 16.0 Hz, 1241, 811 1H), 6.30 (dd, J = 16.0, 8.0Hz, 1H), 5.81 (br, 1H), 5.48 (m, 1H), 4.10 (m, 1H), 3.10 (m, 2H),2.86-3.07 (m, 2H), 2.86 (m, 1H), 1.81 (m, 1H); BC5 544.25 7.40 (s, 2H),7.21 (s, 3489, 3291, ([M − H]⁻) 1H), 7.12 (m, 1H), 1655, 1112, 6.56 (d,J = 16.0 Hz, 1H), 808 6.32 (dd, J = 16.0, 8.4 Hz, 1H), 5.85 (br s, 1H),5.23 (br s, 1H), 4.12 (m, 1H), 3.18 (m, 3H), 2.80 (m, 3H), 2.08 (m, 2H),1.83 (m, 5H), 1.25 (m, 2H), 1.01 (m, 3H), 0.78 (m, 2H) BC6 485.96 7.40(s, 2H), 3429, 1114, ([M − H]⁻) 7.31-7.18 (m, 3H), 6.58 (d, J = 16.0 Hz,804 1H), 6.24-6.28 (dd, J = 16.0, 8.0 Hz, 1H), 5.40 (br, 1H), 4.01 (m,2H), 2.78-3.01 (m, 2H), 2.51 (s, 1H), 1.86 (m, 1H), 1.20 (m, 2H), 1.01(m, 2H), 0.78 (m, 2H) BC7 500.01 7.40 (s, 2H), 7.31 (s, 3296, 1115, ([M− H]⁻) 1H), 7.18 (m, 1H), 806 7.18 (s, 1H), 6.58 (d, J = 16.0 Hz, 1H),6.32 (dd, J = 16.0, 8.0 Hz, 1H), 5.78 (br s, 1H), 5.21 (br s, 1H), 4.01(m, 1H), 2.78 (m, 2H), 2.01 (m, 1H), 1.86 (m, 4H), 1.25 (m, 2H), 1.01(m, 3H), 0.78 (m, 2H) BC8 511.88 7.38-7.20 (m, 5H), 1657, 1113, ([M −H]⁻) 6.62 (d, J = 16.0 Hz, 1H), 855 6.34 (dd, J = 16.0, 8.0 Hz, 1H),5.83 (br, 1H), 5.52 (m, 1H), 4.12 (m, 1H), 3.12 (m, 2H), 3.06-2.82 (m,2H), 2.75 (m, 1H), 1.85 (m, 1H) BC9 179-181 556.83 8.30 (s, 1H), 7.68(d, J = 6.4 Hz, ([M − H]⁻) 1H), 7.38-7.20 (m, 5H), 6.60 (d, J = 16.0 Hz,1H), 6.34 (dd, J = 16.0, 8.0 Hz, 1H), 5.63 (br, 1H), 5.52 (m, 1H), 4.12(m, 1H), 3.56 (s, 2H), 3.06-2.82 (m, 2H), 2.70 (m, 1H), 1.82 (m, 1H)BC10 497.98 7.38-7.20 (m, 5H), 3027, 1654, ([M − H]⁻) 6.62 (d, J = 16.0Hz, 1H), 815 6.34 (dd, J = 16.0, 8.0 Hz, 1H), 5.83 (br, 1H), 5.52 (m,1H), 4.12 (m, 1H), 3.02 (m, 3H), 2.82 (m, 1H), 2.50 (m, 3H), 1.82 (m,1H), 1.42 (m, 1H) BC11 530.09 7.80 (m, 1H), 7.48 (m, 1715, 1113, ([M −H]⁻) 2H), 7.32 6.65 (d, J = 16.0 Hz, 816 1H), 6.54 (dd, J = 16.0, 8.0Hz, 1H), 5.38 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.32 (m, 1H), 2.86(m, 1H), 1.81 (m, 1H) BC12 514.86 7.32, (d, J = 6.0 Hz, 2H) 3428, 1112,([M + H]⁺) 7.28 (m, 1H), 7.20 (d, J = 8.0, 857 1H), 7.14 (d, J = 8.8,1H), 6.70 (d, J = 8.0 Hz, 1H), 6.60 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H),3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); BC13 121-126 553.06 8.33 (br,1H), 7.59 (s, ([M − H]⁻) 1H), 7.45 (m, 3H), 6.72 (d, J = 3.6, 1H), 6.39(m, 1H), 4.71 (t, J = 7.2 Hz, 2H), 4.15 (m, 2H) BC14 172-175 554.0 8.83(t, J = 6.6 Hz, 1H), ([M − H]⁻) 8.42 (t, J = 14.7 Hz, 1H), 8.22 (d, J =8.1 Hz, 1H), 8.13 (t, J = 6.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.16-7.07 (m,1H), 7.01-6.93 (m, 1H), 4.96-4.81 (m, 3H), 4.00-3.88 (m, 2H) CC1 107-109402.00 7.37 (m, 3H), 7.28 (m, ([M + H]⁺) 4H), 6.60 (d, J = 16.0 Hz, 1H),6.36 (dd, J = 16.0, 8.0 Hz, 1H), 5.75 (br s, 1H), 4.46 (d, J = 6 Hz,2H), 4.01 (m, 1H), 2.11 (s, 3H) CC2 118-120 428.11 7.37 (m, 3H), 7.28(m, ([M + H]⁺) 4H), 6.60 (d, J = 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.0Hz, 1H), 5.83 (br s, 1H), 4.46 (d, J = 6.0 Hz, 2H), 4.11 (m, 1H), 1.40(m, 1H), 1.02 (m, 2H), 0.77 (m, 2H) CC3 119-122 468.20 7.38 (m, 3H),7.27 (m, ([M − H]⁻) 3H), 6.60 (d, J = 16.0 Hz, 1H), 6.36 (dd, J = 16.0,8.4 Hz, 1H), 5.00 (br s, 1H), 4.48 (d, J = 5.6 Hz, 2H), 4.11 (m, 1H),3.15 (q, J = 10.4 Hz, 2H) CC4 414.16 7.37 (m, 3H), 7.28 (m, ([M − H]⁻)3H), 6.60 (d, J = 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 5.69(br s, 1H), 4.46 (d, J = 6.0 Hz, 2H), 4.21 (m, 1H), 2.29 (q, J = 5.8 Hz,2H), 1.30 (t, J = 7.2 Hz, 3H) CC5 460.28 7.40 (m, 3H), 7.28 (m, ([M −H]⁻) 2H), 6.60 (d, J = 15.6 Hz, 1H), 6.33 (dd, J = 15.6, 8.0 Hz, 1H),5.84 (br s, 1H), 4.46 (d, J = 5.6 Hz, 2H), 4.10 (m, 1H), 1.36 (m, 1H),1.02 (m, 2H), 0.77 (m, 2H) CC6 106-108 504.08 7.40 (m, 3H), 7.26 (m, ([M− H]⁻) 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.34 (dd, J = 16.0, 8.0 Hz, 1H),5.96 (br s, 1H), 4.49 (d, J = 5.6 Hz, 2H), 4.10 (m, 1H), 3.15 (q, J =10.8 Hz, 2H) CC7 127-128 436.03 7.42 (m, 4H), 7.24 (m, ([M + H]⁺) 2H),6.53 (d, J = 16.0 Hz, 1H), 6.36 (dd, J = 16.0, 8.0 Hz, 1H), 5.86 (br s,1H), 4.51 (d, J = 6.0 Hz, 2H), 4.05 (m, 1H), 2.02 (s, 3H) CC8 129-131462.15 8.58 (t, J = 5.6 Hz, 1H), ([M + H]⁺) 7.72 (m, 1H), 7.66 (m, 3H),7.49 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.90 (dd, J = 16.0,8.0 Hz, 1H), 6.73 (d, J = 16 Hz, 1H), 4.81 (m, 1H), 4.33 (d, J = 6.0 Hz,1H), 1.64 (m, 1H), 0.68 (m, 4H) CC9 132-134 504.25 7.41 (m, 3H), 7.26(m, ([M + H]⁺) 3H), 6.54 (d, J = 16.0 Hz, 1H), 6.37 (dd, J = 16.0, 8.0Hz, 1H), 6.13 (br s, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.11 (m, 1H), 3.13(m, 2H) CC10 538.03 7.38 (m, 4H), 6.56 (d, J = 16.0 Hz, 1651, 1112,([M + 2H]⁺) 1H), 807 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 6.18 (m, 1H), 4.58(m, 2H), 4.08 (m, 1H), 3.08 (m, 2H) CC11 111-112 494.12 7.42 (m, 3H),7.24 (m, ([M − H]⁻) 1H), 6.54 (d, J = 15.6 Hz, 1H), 6.34 (dd, J = 16.0,8.0 Hz, 1H), 6.03 (m, 1H), 4.53 (d, J = 6.0 Hz, 1H), 4.10 (m, 1H), 1.39(m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) CC12 76-78 510.07 7.39 (s, 4H), 7.34(d, J = 8.0 Hz, ([M − H]⁻) 1H), 7.26 (m, 1H), 6.57 (d, J = 16.0 Hz, 1H),6.35 (dd, J = 16.0, 8.0 Hz, 1H), 6.10 (br s, 1H), 4.49 (d, J = 6.0 Hz,2H), 4.10 (m, 1H), 1.20 (s, 9H) CC13 73-76 563.37 8.51 (d, J = 5.2 Hz,1H), ([M − H]⁻) 7.63 (s, 1H), 7.51 (m, 1H), 7.45 (m, 2H), 7.39 (s, 2H),7.28 (m, 1H), 6.58 (m, 2H), 6.37 (dd, J = 16.0, 8.0 Hz, 1H), 4.71 (d, J= 6.0 Hz, 1H), 4.11 (m, 1H) CC14 581.45 8.51 (m, 1H), 8.30 (d, J = 2.4Hz, 3430, 1656, ([M + 1H]⁺) 1H), 7.73 (m, 1109, 806 1H), 7.61 (s, 2H),7.51 (s, 1H), 7.32 (m, 3H), 6.66 (d, J = 16.0 Hz, 1H), 6.56 (dd, J =16.0, 8.4 Hz, 1H), 4.50 (m, 1H), 4.45 (d, J = 5.6 Hz, 1H), 3.56 (s, 2H)CC15 480.24 7.40 (m, 3H), 7.33 (m, 3293, 1651, ([M + H]⁺) 1H), 7.22 (m,2H), 1543, 1114, 6.54 (d, J = 15.6 Hz, 1H), 812 6.34 (dd, J = 16.0, 8.0Hz, 1H), 6.03 (br s, 1H), 4.53 (d, J = 6.0 Hz, 2H), 4.13 (m, 1H), 1.41(m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) CC16 520.33 7.42 (s, 1H), 7.37 (m,3307, 1665, ([M − H]⁻) 3H), 7.22 (m, 1H), 1114, 813 6.54 (d, J = 16.0Hz, 1H), 6.36 (dd, J = 16.0, 8.0 Hz, 1H), 6.19 (br s, 1H), 4.51 (d, J =6.0 Hz, 2H), 4.21 (m, 1H), 3.33 (m, 2H) CC17 117-119 459.83 7.51 (m,2H), 7.39 (m, 3293, 1633, ([M − H]⁻) 2H), 7.24 (m, 2H), 1110, 820 6.52(d, J = 15.6 Hz, 1H), 6.38 (dd, J = 15.6, 7.6 Hz, 1H), 6.02 (br s, 1H),4.53 (d, J = 6.0 Hz, 2H), 4.14 (m, 1H), 1.38 (m, 1H)), 1.00 (m, 2H),0.77 (m, 2H) CC18 119-123 501.88 7.48 (m, 2H), 7.41 (s, 3435, 1644, ([M− H]⁻) 1H), 7.36 (d, J = 8.0 Hz, 1111, 817 1H), 7.23 (m, 2H), 6.52 (d, J= 16.0 Hz, 1H), 6.39 (dd, J = 16.0, 8.0 Hz, 1H), 6.13 (br s, 1H), 4.56(d, J = 6.0 Hz, 2H), 4.15 (m, 1H), 3.13 (m, 2H) CC19 530 7.41 (m, 2H),7.24 (m, 3435, 1644, ([M + H]⁺) 1H), 6.53 (d, J = 16.0 Hz, 1111, 8171H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 4.53 (m, 2H), 4.10 (m, 1H), 3.42(m, 2H), 2.97 (s, 3H), 2.78 (m, 2H) CC20 512 7.42 (m, 3H), 7.24 (m,3293, 1633, ([M + H]⁺) 1H), 6.54 (d, J = 15.6 Hz, 1110, 820 1H), 6.34(dd, J = 15.6, 8.0 Hz, 1H), 6.03 (m 1H), 4.53 (d, J = 6.0 Hz, 1H), 4.10(m, 1H), 1.19 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) CC21 55-58 493.99(DMSO-d₆) 8.62 (m, ([M − H]⁻) 1H), 7.95 (s, 1H), 7.85 (m, 1H), 7.66 (m,3H), 7.47 (d, J = 8.0 Hz, 1H), 6.98 (dd, J = 16.0, 8.0 Hz, 1H), 6.84 (d,J = 16.0 Hz, 1H), 4.83 (m, 1H), 4.44 (s, 2H), 1.68 (m, 1H), 0.71 (m, 4H)CC22 67-69 530.01 8.62 (m, 1H), 7.90 (s, ([M + H]⁺) 3H), 7.82 (m, 1H),7.45 (m, 1H), 6.98 (m, 1H), 6.84 (d, J = 16.0 Hz, 1H), 4.82 (m, 1H), 4.4(s, 2H), 1.66 (m, 1H), 0.72 (m, 4H) CC23 69-71 564.99 9.02 (br s, 1H),8.54 (br ([M − H]⁻) s, 1H), 8.26 (br s, 1H), 7.48-7.54 (m, 3H),7.22-7.42 (m, 3H), 6.59-6.62 (m, 2H), 6.38-6.42 (m, 1H), 4.82 (m, 2H),4.19 (s, 1H) CC24 125-127 570.26 7.64 (s, 1H), 7.54 (s, ([M − H]⁻) 2H),7.46 (s, 2H), 6.62 (d, J = 16.0 Hz, 1H), 6.41 (dd, J = 16.0, 8.4 Hz,1H), 6.03 (m, 1H), 4.65 (d, J = 6.4 Hz, 2H), 4.14 (m, 1H,), 3.13 (q, J =10.6 Hz, 2H) CC25 579.86 7.60 (s, 1H), 7.40 (s, 3297, 1663, ([M − H]⁻)2H), 7.37 (d, J = 8.0 Hz, 1114, 809 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.53(d, 1H, J = 16.0 Hz), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 6.17 (br s, 1H),4.56 (d, J = 6.4 Hz, 2H), 4.12 (m, 1H), 3.15 (q, J = 10.6 Hz, 2H) CC26129-131 539.89 7.59 (s, 1H), 7.39 (m, ([M + H]⁺) 2H), 7.30 (s, 1H), 6.53(d, J = 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 6.06 (br s, 1H),4.42 (d, J = 4.4 Hz, 2H), 4.12 (m, 1H), 1.35 (br s, 1H), 0.95 (br s,2H), 0.75 (m, 2H) CC27 519.95 7.39 (s, 2H), 7.33 (t, J = 7.6 Hz, 3306,1786 ([M − H]⁻) 1H), 7.14 (m, 2H), 6.56 (d, J = 16.0 Hz, 1H), 6.35 (dd,J = 16.0, 7.6 Hz, 1H), 6.06 (br s, 1H), 4.52 (d, J = 16.0 Hz, 2H), 4.08(m, 1H), 3.90 (s, 2H), 3.13 (m, 2H) CC28 477.93 7.39 (s, 2H), 7.35 (m,3625, 1747 ([M − H]⁻) 1H), 7.14 (m, 2H), 6.55 (d, J = 15.6 Hz, 1H), 6.33(dd, J = 15.6, 8.0 Hz, 1H), 5.93 (br s, 1H), 4.49 (d, J = 16.0 Hz, 2H),4.10 (m, 1H), 1.36 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) CC29 620.86 8.58(d, J = 4.6 Hz, 1H), 1645, 1115, ([M − H]⁻) 7.74 (m, 1H), 7.62 (m, 8082H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J =16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 5.02 (s, 1H), 4.8 (s,1H), 4.8 (d, J = 10 Hz, 2H), 4.10 (m, 1H), 1.8 (m, 1H), 1.2 (m, 2H), 0.6(m, 2H) CC30 101-104 559.75 7.41 (m, 4H), 7.24 (m, ([M − H]⁻) 1H), 6.53(d, J = 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 6.12 (br s, 1H),4.53 (m, 2H), 4.10 (m, 1H), 3.42 (m, 2H), 2.91 (s, 3H), 2.78 (m, 2H)CC31 177-178 463 7.58 (m, 2H), 7.41 (m, ([M − H]⁻) 3H), 7.24 (m, 1H),6.53 (d, J = 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 4.70 (br s,1H), 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H); CC32141-142 532.99 7.66 (m, 2H), 7.54 (m, ([M + H]⁺) 1H), 7.41 (s, 2H), 6.62(d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 4.59 (s, 3H),4.19 (m, 1H), 3.25 (m, 2H), 1.15 (m, 2H) CC33 540.88 7.57 (s, 1H), 7.40(m, 3338, 1631, ([M − H]⁻) 2H), 7.30 (s, 1H), 1578, 1114, 7.20 (br s,1H), 6.53 (d, J = 16.0 Hz, 809 1H), 6.33 (dd, J = 16.0, 8.0 Hz, 1H),6.06 (br s, 1H), 4.75 (br s, 1H), 4.42 (s, 2H), 4.20 (br s, 1H), 4.15(m, 2H), 3.20 (m, 2H), 1.15 (m, 3H) CC34 118-120 541.40 7.42 (m, 3H),7.28 (m, ([M + H]⁺) 2H), 6.54 (d, J = 16.0 Hz, 1H), 6.36 (dd, J = 16.0,8.0 Hz, 1H), 4.96 (m, 1H), 4.51 (d, J = 5.6 Hz, 2H), 4.12 (m, 1H), 3.69(t, J = 4.8 Hz, 4H), 3.35 (t, J = 4.8 Hz, 1H) CC35 78-79 547.82 9.95 (brs, 1H), 8.17 (d, ([M + H]⁺) J = 4.8 Hz, 1H), 7.61 (d, J = 6.4 Hz), 7.43(m, 3H), 7.24 (m, 2H), 6.90 (t, J = 5.6 Hz, 1H), 6.66 (d, J = 8.4 Hz,1H), 6.54 (d, J = 16.0 Hz, 1H), 6.33 (dd, J = 16.0, 8.0 Hz, 1H), 4.65(d, J = 6.0 Hz, 1H), 4.09 (m, 1H) CC36 497 7.39 (m, 4H), 7.28 (m, 3350,1705, ([M − H]⁻) 1H), 6.54 (d, J = 16.0 Hz, 1114, 808 1H), 6.34 (dd, J =16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J = 6.0 Hz, 2H), 4.10 (m,1H), 2.9 (s, 3H), 2.7 (s, 3H) CC37 88-91 515.01 7.49 (d, J = 8 Hz, 1H),([M + H]⁺) 7.41 (d, J = 7.2 Hz, 2H), 7.26 (m, 2H), 6.50 (d, J = 16 Hz,1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 6.0 (brs, 1H), 5.73 (br s, 1H),4.80 (br s, 2H), 4.09 (m, 1H), 1.23 (m, 3H) CC38 63-66 526.97 7.48 (d, J= 8 Hz, 1H), ([M + H]⁺) 7.39 (m, 3H), 7.27 (m, 1H), 6.54 (d, J = 16 Hz,1H), 6.33 (dd, J = 6.0, 8.0 Hz, 1H), 6.17 (br s, 1H), 5.92 (br s, 1H),5.83 (m, 2H), 5.29 (t, J = 15.4 Hz, 2H), 4.80 (br s, 2H), 4.12 (m, 1H),4.02 (br s, 2H) CC39 526.09 7.39 (m, 4H), 7.28 (m, 3350, 1705, ([M −H]⁻) 1H), 6.54 (d, J = 16.0 Hz, 1114, 808 1H), 6.34 (dd, J = 16.0, 8.0Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J = 6.0 Hz, 2H), 4.10 (m, 1H), 1.53(s, 9H) CC40 159-160 580.25 7.46 (m, 5H), 7.29 (m, ([M − H]⁻) 1H), 7.20(m, 3H), 6.55 (d, J = 16.0 Hz, 1H), 6.37 (dd, J = 16.0, 8.0 Hz, 1H),5.62 (br s, 1H), 4.55 (d, J = 6.4 Hz, 2H), 4.11 (m, 1H) CC41 512.22 7.48(m, 1H), 7.43 (m, 1740, 1701, ([M − H]⁻) 3H), 7.38 (m, 1H), 1114, 8087.23 (s, 1H), 6.55 (d, J = 16.0 Hz, 1H), 6.36 (d, J = 16.0 Hz, 1H), 4.60(d, 2H), 4.18 (m, 1H), 3.85 (s, 3H) CC42 161-163 578.96 (DMSO-d₆) 9.45(br s, ([M − H]⁻) 2H), 7.90 (s, 2H), 7.75 (s, 1H), 7.46 (br s, 1H), 7.28(br s, 1H), 6.93 (m, 1H), 6.75 (br s, 1H), 4.80 (m, 1H), 4.40 (br s,2H), 3.90 (br s, 2H) CC43 140-142 505.39 8.11 (d, J = 4.0 Hz, 1H), ([M +H]⁺) 7.40 (m, 5H), 7.22 (m, 1H), 6.61 (m, 2H), 6.35 (m, 2H), 4.94 (br s,1H) 4.61 (d, J = 6.4 Hz, 2H), 4.11 (m, 1H) CC44 536.88 8.41 (s, 1H),7.77 (s, 3320, 1674, ([M − H]⁻) 1H), 7.47 (br s, 1H), 1114, 808 7.40 (s,2H), 6.58 (d, J = 16.0 Hz, 1H), 6.45 (dd, J = 16.0, 8.0 Hz, 1H), 4.68(d, J = 4.0 Hz, 2H), 4.14 (m, 1H), 3.24 (q, J = 10.8 Hz, 2H) CC45 494.888.41 (s, 1H), 7.76 (s, 3309, 1659, ([M − H]⁻) 1H), 7.40 (s, 2H), 1115,808 7.15 (br s, 1H), 6.58 (d, J = 16.0 Hz, 1H), 6.44 (dd, J = 16.0, 8.0Hz, 1H), 4.67 (d, J = 4.4 Hz, 2H), 4.16 (m, 1H), 1.57 (m, 1H), 1.04 (m,2H), 0.87 (m, 2H) CC46 151-153 554.04 8.06 (m, 1H), 7.61 (m, ([M − H]⁻)4H), 7.48 (s, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (m, 1H), 6.42 (m, 1H),5.92 (br s, 1H), 4.92 (m, 2H), 4.24 (m, 1H), 3.12 (m, 2H) CC47 478.098.06 (m, 2H), 7.61 (m, 3309, 1659, ([M + H]⁺) 4H), 7.48 (s, 2H), 1115,808 7.44 (d, J = 8.0 Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H),1.36 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) CC48 511.05 8.06 (m, 2H), 7.61(m, 3309, 1659, ([M + H]⁺) 3H), 7.48 (s, 2H), 1115, 808 7.44 (d, J = 8.0Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H), 1.36 (m, 1H), 1.00(m, 2H), 0.77 (m, 2H) CC49 84-87 515.33 8.06 (m, 1H), 7.98 (m, ([M +H]⁺) 1H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (m,2H), 6.42 (m, 1H), 4.92 (s, 2H), 4.6 (br s, 1H), 4.24 (m, 1H), 3.21 (m,2H), 1.2 (t, J = 4.6 Hz, 3H) CC50 138-140 461.32 9.81 (s, 1H), 7.90 (s,([M − 1H]⁻) 1H), 7.84 (s, 2H), 7.34 (d, J = 8.4 Hz, 2H), 6.65 (d, J =15.6 Hz, 1H), 6.61 (m, 1H), 6.57 (s, 1H), 6.48 (dd, J = 15.6, 8.8 Hz,1H), 4.74 (m, 1H), 1.64 (m, 1H), 0.75 (m, 4H); CC51 149-150 505.31 7.56(br s, 1H), 7.4 (s, ([M − H]⁻) 3H), 7.3 (m, 3H), 7.05 (br s, 1H), 6.8(d, J = 6 Hz, 2H), 6.57 (m, 2H), 6.20 (m, 2H), 4.05 (m, 1H), 3.2 (q, J =10.4 Hz, 2H) CC52 464.87 7.40 (s, 2H), 7.18 (s, 3309, 1659, ([M − H]⁻)1H), 7.08 (s, 1H), 1115, 808 6.85 (m, 1H), 6.45 (m, 1H), 6.20 (m, 1H),5.55 (s, 1H), 4.08 (m, 1H), 1.30-1.10 (m, 4H), 1.90 (m, 1H) CC53 5067.40 (s, 2H), 7.18 (s, 3309, 1659, ([M + H]⁺) 1H), 7.08 (s, 1H), 1115,808 6.85 (m, 1H), 6.45 (m, 1H), 6.20 (m, 1H), 5.55 (s, 1H), 4.08 (m,1H), 3.21 (m, 2H) CC54 504 7.28 (s, 2H), 7.25 (m, ([M + H]⁺) 2H), 7.10(d, J = 8.0 Hz, 2H), 6.89 (d, J = 11.4 Hz, 1H), 6.07 (br s, 1H), 6.01(m, 1H), 4.51 (d, J = 5.8 Hz, 2H), 4.34 (m, 1H), 3.12 (q, J = 7.5 Hz,2H) DC1 93-97 398.05 8.56 (s, 1H), 8.11 (s, ([M + H]⁺) 1H), 7.68 (d, J =8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.38 (t, J = 1.8 Hz, 1H), 7.29(s, 2H), 6.62 (d, J = 15.6 Hz, 1H), 6.42 (dd, J = 15.6, 8.2 Hz, 1H),4.15 (m, 1H) DC2 363.0746 8.59 (s, 1H), 8.13 (s, 3121, 1524, (363.075)1H), 7.69 (d, J = 8.5 Hz, 1251, 1165, 2H), 7.55 (d, J = 8.5 Hz, 11192H), 7.41-7.29 (m, 4H), 6.64 (d, J = 15.7 Hz, 1H), 6.47 (dd, J = 15.9,8.0 Hz, 1H), 4.17 (m, 1H) DC3 329.1144 8.56 (s, 1H), 8.11 (s, 1521,1246, (329.114) 1H), 7.65 (d, J = 8.4 Hz, 1219, 1162, 2H), 7.52 (d, J =8.3 Hz, 1152, 1107 2H), 7.40 (m, 5H), 6.61 (d, J = 15.8 Hz, 1H), 6.51(dd, J = 15.9, 7.7 Hz, 1H), 4.18 (m, 1H) DC4 364.11 8.56 (s, 1H), 8.10(s, 3147, 1528, ([M + H]⁺) 1H), 7.66 (d, J = 2.0 Hz, 1494, 1246, 2H),7.52 (d, J = 8.8 Hz, 1165, 1108 2H), 7.38 (d, J = 2.4 Hz, 2H), 7.34 (d,J = 8.4 Hz, 2H), 6.61 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 7.6 Hz,1H), 4.15 (m, 1H) DC5 344.25 8.54 (s, 1H), 8.10 (s, 3122, 3047, ([M +H]⁺) 1H), 7.62 (d, J = 8.3 Hz, 1523, 1252, 2H), 7.50 (d, J = 8.4 Hz,1160, 1107 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.60(d, J = 16.0 Hz, 1H), 6.51 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H),2.37 (s, 3H) DC6 360.28 8.55 (s, 1H), 8.10 (s, 3124, 2936, ([M + H]⁺)1H), 7.65 (d, J = 8.8 Hz, 1522, 1249, 2H), 7.52 (d, J = 8.8 Hz, 11602H), 7.32 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.60 (d, J =16.0 Hz, 1H), 6.56 (dd, J = 16.0, 7.4 Hz, 1H), 4.15 (m, 1H), 3.82 (s,3H) DC7 348 8.55 (s, 1H), 8.10 (s, 3141, 1512, ([M + H]⁺) 1H), 7.62 (d,J = 8.8 Hz, 1246, 1118 2H), 7.5 (d, J = 8.4 Hz, 2H), 7.38 (m, 2H), 7.12(m, 2H), 6.61 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 7.6 Hz, 1H),4.15 (m, 1H) DC8 366.13 8.57 (s, 1H), 8.11 (s, 3116, 1628, ([M + H]⁺)1H), 7.65 (d, J = 7.2 Hz, 1524, 1252, 2H), 7.52 (d, J = 8.0 Hz, 1168,1118 2H), 6.95 (m, 2H), 6.82 (m, 1H), 6.65 (d, J = 16.0 Hz, 1H), 6.50(dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H) DC9 348.11 8.71 (s, 1H), 8.20(s, 3115, 1525, ([M + H]⁺) 1H), 7.70 (d, J = 8.0 Hz, 1248, 1174 2H),7.57 (d, J = 8.0 Hz, 2H), 7.40 (m, 1H), 7.19 (m, 3H), 6.60 (d, J = 16.0Hz, 1H), 6.40 (dd, J = 16.0, 8.4 Hz, 1H), 4.15 (m, 1H) DC10 348.11 8.75(s, 1H), 8.20 (s, 3114, 1526, ([M + H]⁺) 1H), 7.72 (d, J = 8.4 Hz, 1259,1238, 2H), 7.6 (d, J = 8.4 Hz, 1193, 1114 2H), 7.20-7.40 (m, 4H), 6.60(d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H, ), 4.60 (m, 1H)DC11 75.5-78.5 358.14 8.55 (s, 1H), 8.10 (s, ([M + H]⁺) 1H), 7.65 (d, J= 8.8 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.01 (s, 3H), 6.60 (d, J = 16.0Hz, 1H), 6.51 (dd, J = 16.0, 7.8 Hz, 1H), 4.15 (m, 1H), 2.34 (s, 6H)DC12 398.05 8.58 (s, 1H), 8.10 (s, 3055, 2930, ([M + H]⁺) 1H), 7.68 (d,J = 8.4 Hz, 1523, 1250, 2H), 7.53 (m, 4H), 1165 7.2 (s, 1H) 6.62 (d, J =15.6 Hz, 1H), 6.44 (dd, J = 15.6, 8.0 Hz, 1H), 4.15 (m, 1H) DC13 396.168.58 (s, 1H), 8.10 (s, 3108, 1523, ([M + H]⁺) 1H), 7.62 (d, J = 8.4 Hz,1249, 1166, 2H), 7.55 (m, 4H), 1127 7.25 (m, 1H), 6.64 (d, J = 16.0 Hz,1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 4.90 (m, 1H) DC14 398.05 8.58 (s,1H), 8.10 (s, 3117, 2925, ([M + H]⁺) 1H), 7.62 (d, J = 8.4 Hz, 1526,1246, 2H), 7.55 (m, 4H), 1172, 1117 7.25 (m, 1H), 6.67 (d, J = 16.0 Hz,1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 5.00 (m, 1H) DC15 397.95 8.58 (s,1H), 8.10 (s, 3120, 1524, ([M + H]⁺) 1H), 7.66 (d, J = 8.0 Hz, 1267,1176, 2H), 7.52 (m, 3H), 1112 7.40 (d, J = 8.0 Hz, 1H), 7.30 (dd, J =8.4, 2.9 Hz, 1H), 6.64 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz,1H), 4.90 (m, 1H) DC16 466 8.61 (s, 1H), 8.13 (s, ([M + H]⁺) 1H), 7.92(s, 1H), 7.86 (s, 2H), 7.70 (d, J = 7.0 Hz, 2H), 7.54 (d, J = 7.0 Hz,2H), 6.67 (d, J = 16.0 Hz, 1H), 6.46 (dd, J = 16.0, 8.0 Hz, 1H), 4.35(m, 1H) DC17 430.06 8.58 (s, 1H), 8.1 (s, 1H), 3122, 3076, ([M + H]⁺)7.68 (d, J = 8.4 Hz, 2H), 2929, 1523, 7.54 (d, J = 8.4 Hz, 2H), 1250,1168, 7.51 (s, 1H), 7.42 (s, 1114 1H), 6.68 (d, J = 16.0 Hz, 1H), 6.35(dd, J = 16.0, 8.0, Hz, 1H), 4.98 (m, 1H) DC18 92-95 429.91 8.57 (s,1H), 8.11 (s, ([M + H]⁺) 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.4Hz, 2H), 7.42 (s, 2H), 6.65 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0,8.0 Hz, 1H), 4.10 (m, 1H) DC19 97-99 430.321 8.58 (s, 1H), 8.12 (s,([M + H]⁺) 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.64 (s, 1H), 7.59 (s, 1H),7.55 (m, 3H), 6.60 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz,1H), 4.22 (m, 1H) DC20 427.0463 8.58 (s, 1H), 8.15 (s, 2937, 1524,(427.0466) 1H), 7.70 (d, J = 8.4 Hz, 1482, 1278, 2H), 7.58 (d, J = 8.4Hz, 1249, 1166, 2H), 7.36 (s, 2H), 1112 6.62 (d, J = 16.0 Hz, 1H), 6.43(dd, J = 16.0, 8.0 Hz, 1H), 4.12 (m, 1H), 3.88 (s, 3H) DC21 412.04 8.42(s, 1H), 7.60 (d, J = 8.0 Hz, 3108, 1572, ([M + H]⁺) 2H), 7.50 (d, J =8.0 Hz, 1531, 1242, 2H), 7.40 (s, 1172, 1104 1H), 7.22 (s, 2H), 6.60 (d,J = 16.0 Hz, 1H), 6.42 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H), 2.5 (s,3H) DC22 147-149 441.01 8.62 (s, 1H), 7.78 (d, J = 8.0 Hz, ([M − H]⁻)2H), 7.60 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 7.30 (s, 2H), 6.67 (d, J =16.0 Hz, 1H), 6.48 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H) DC23 412.057.95 (s, 1H), 7.35 (d, J = 8.0 Hz, 1112, 799 ([M + H]⁺) 2H), 7.46 (d, J= 8.0 Hz, 2H), 7.39 (s, 1H), 7.29 (s, 2H), 6.67 (d, J = 16.0 Hz, 1H),6.45 (dd, J = 16.0, 8.0 Hz, 1H), 4.12 (m, 1H), 2.51 (s, 3H) DC24 133-134440.03 8.10 (s, 1H), 7.52 (d, J = 8.0 Hz, ([M + H]⁺) 2H), 7.42-7.38 (m,3H), 7.28 (s, 2H), 6.67 (d, J = 16.0 Hz, 1H), 6.45 (dd, J = 16.0, 8.0Hz, 1H), 4.16 (m, 1H), 2.79 (s, 3H) DC25 442.02 7.97 (s, 1H), 7.59 (d, J= 8.0 Hz, 1167, 1114, ([M − H]⁻) 2H), 7.53 (d, J = 8.0 Hz, 800 2H), 7.38(m, 1H), 7.29 (s, 2H), 6.65 (d, J = 16.0 Hz, 1H), 6.42 (dd, J = 16.0,8.0 Hz, 1H), 4.17 (m, 1H), 2.74 (s, 3H) DC26 464.03 8.12 (s, 1H), 7.49(d, J = 8.0 Hz, 1689, 1253, ([M − H]⁻) 2H), 1166, 1114, 7.40-7.37 (m3H), 7.28 (s, 2H), 979, 964 6.66 (d, J = 16.0 Hz, 1H), 6.44 (dd, J =16.0, 8.0 Hz, 1H), 4.14 (m, 1H), 3.22 (m, 1H), 1.09-1.16 (m, 4H) DC27473.94 8.19 (s, 1H), 7.64 (d, J = 7.2 Hz, 1571, 1331, ([M − H]⁻) 2H),7.55 (d, 7.2 Hz, 1170, 1113, 2H), 7.39 (s, 1H), 764 7.30 (s, 2H), 6.62(d, J = 16.0 Hz, 1H), 6.42 (dd, J = 8.0, 16.0 Hz, 1H), 4.18 (m, 1H),3.58 (s, 3H) DC28 421.22 8.79 (s, 1H), 8.18 (s, 3126, 2233, ([M + H]⁺)1H), 7.80 (m, 3H), 1516, 1250, 7.52 (m, 2H), 7.24 (m, 1H), 1165, 11096.63 (d, J = 16.0 Hz, 1H), 6.54 (d, J = 16.0, 7.6 Hz, 1H), 4.19 (m, 1H)DC29 421.22 8.80 (s, 1H), 8.2 (s, 1H), 3005, 1716, ([M + H]⁺) 7.75-7.82(m, 3H), 1363, 1223 7.41 (t, J = 2 Hz, 1H), 7.26 (m, 2H), 6.65 (d, J =16.0 Hz, 1H), 6.52 (dd, J = 16.0, 7.6 Hz, 1H), 4.16 (m, 1H) DC30 489.178.81 (s, 1H), 8.20 (s, 2964, 2234, ([M + H]⁺) 1H), 7.94 (s, 1H), 1289,1166, 7.85 (m, 3H), 7.79 (m, 2H), 1136 6.70 (d, J = 16.0 Hz, 1H), 6.58(dd, J = 16.0, 8.0 Hz, 1H), 4.35 (m, 1H) DC31 117-118 455.27 8.80 (s,1H), 8.20 (s, ([M + H]⁺) 1H), 7.82 (m, 3H), 7.4 (s, 2H), 6.62 (d, J =16.0 Hz, 1H), 6.52 (dd, J = 16.0, 8.0 Hz, 1H), 4.18 (m, 1H) DC32388.0705 8.82 (s, 1H), 8.22 (s, 3126, 2234, (388.0703) 1H), 7.82-7.78(m, 3H), 1520, 1280, 7.38-7.30 (m, 3H), 1164, 1112 6.62 (d, J = 16.1 Hz,1H), 6.56 (dd, J = 16.1, 6.8 Hz, 1H), 4.18 (m, 1H) DC33 455.22 8.80 (s,1H), 8.20 (s, 3122, 3086, ([M − H]⁻) 1H), 7.82-7.80 (m, 3H), 2234, 1517,7.70-7.50 (m, 3H), 1327, 1168, 6.65 (d, J = 16.9 Hz, 1H), 1113 6.54 (dd,J = 16.9, 6.8 Hz, 1H), 4.25 (m, 1H) DC34 452.0412 8.85 (s, 1H), 8.23 (brs, 3122, 2934, (452.0419) 1H), 7.83-7.78 (m, 3H), 2231, 1516, 7.33 (s,2H), 6.69 (d, J = 14.9 Hz, 1480, 1248, 1H), 6.50 (dd, 1211, 1165, J =14.9, 7.2 Hz, 1H), 1111 4.15 (m, 1H), 3.90 (s, 3H) DC35 439.01 8.60 (s,1H), 8.20 (s, 2233, 1518, ([M − H]⁻) 1H), 7.82 (m, 3H), 1250, 1169, 7.28(m, 2H), 6.65 (d, J = 16.0 Hz, 1035, 817 1H), 6.48 (dd, J = 16.0, 8.0Hz, 1H), 4.20 (m, 1H) DC36 437.25 8.70 (s, 1H), 7.80 (m, 2927, 2233,([M + H]⁺) 3H), 7.40 (s, 1H), 1572, 1531, 7.28 (s, 2H), 6.63 (d, J =16.0 Hz, 1248, 1166, 1H), 6.50 (dd, J = 16.0, 1112 8.0 Hz, 1H), 4.18 (m,1H), 2.50 (s, 1H) DC37 109-111 466.10 8.86 (s, 1H), 7.89 (m, ([M − H]⁻)3H), 7.40 (s, 1H), 7.30 (s, 2H), 6.68 (d, J = 16.0 Hz, 1H), 6.57 (dd, J= 16.0, 8.0 Hz, 1H), 4.18 (m, 1H) DC38 96-98 436.11 8.58 (s, 1H), 7.75(m, ([M − H]⁻) 3H), 7.40 (s, 1H), 7.28 (s, 2H), 6.61 (d, J = 16.0 Hz,1H), 6.42 (dd, J = 16.0, 8.2 Hz, 1H), 4.40 (br s, 2H), 4.15 (m, 1H) DC39224-226 480.30 8.65 (s, 1H), 8.18 (br s, 3352, 2237, ([M + H]⁺) 1H),7.80-7.70 (m, 3H), 1707, 1163, 7.40 (s, 1H), 7.27 (s, 841 2H), 7.36 (m,1H), 7.28 (m, 2H), 6.60 (d, J = 16.8 Hz, 1H), 6.47 (m, 1H), 4.16 (m,1H), 2.40 (br s, 3H) DC40 70-73 436.11 8.86 (s, 1H), 7.88 (m, ([M −2H]⁻) 3H), 7.44 (s, 2H), 6.67 (d, J = 16.0 Hz, 1H), 6.56 (dd, J = 16.07.6 Hz, 1H), 4.19 (m, 1H) DC41 72-75 469.95 (DMSO-d₆) 8.72 (s, ([M −H]⁻) 1H), 8.26 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.91 (s, 2H), 7.77 (d,J = 8.4 Hz, 1H), 6.42 (dd, J = 15.6, 9.2 Hz, 1H), 6.83 (d, J = 15.6 Hz,1H), 5.87 (s, 2H), 4.89 (m, 1H) DC42 104-107 609.98 8.78 (s, 2H), 7.83(s, 2234, 1714, ([M + H]⁺) 1H), 7.80 (m, 2H), 1114, 807 7.42 (s, 2H),6.65 (d, J = 16.4 Hz, 1H), 6.51 (dd, J = 16.4, 7.8 Hz, 1H), 4.17 (m,1H), 42.16 (m, 2H), 1.25 (m, 4H), 1.00 (m, 4H), DC43 109-112 540.04(DMSO-d₆) 10.94 (br s, 3233, 2233, ([M + H]⁺) 1H), 8.36 (s, 1H), 1699,1114, 8.08 (m, J = 8.4 Hz, 1H), 807 7.91 (s, 2H), 7.84 (d, J = 8.4 Hz,1H), 7.13 (dd, J = 15.6, 9.2 Hz, 1H), 6.87 (d, J = 15.6 Hz, 1H), 4.92(m, 1H), 1.99 (br s, 1H), 0.82 (s, 4H) DC44 435.26 8.33 (s, 1H), 8.23(s, 2236, 1510, [M − H]⁻ 1H), 7.66 (s, 1H), 1114, 801 7.60 (s, 1H), 7.41(m, 1H), 7.28 (m, 2H), 6.62 (d, J = 16.0 Hz, 1H), 6.51 (dd, J = 16.0,7.8 Hz, 1H), 4.16 (m, 1H), 2.20 (s, 3H) DC45 75-78 468.87 8.36 (s, 1H),8.23 (s, [M − H]⁻ 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.41 (s, 2H), 6.62(d, J = 16.4 Hz, 1H), 6.51 (dd, J = 16.4, 7.6 Hz, 1H), 4.16 (m, 1H),2.20 (s, 3H) DC46 411.4 8.83 (s, 1H), 8.21 (s, ¹³C NMR (δ)³ ([M]⁺) 1H),7.83 (d, J = 8.5 Hz, 155.63, 1H), 7.61 (d, J = 1.9 Hz, 153.27, 1H), 7.52(dd, J = 8.4, 153.12, 1.9 Hz, 1H), 7.28 (d, J = 3.8 Hz, 143.01, 2H),6.93 (d, J = 11.5 Hz, 137.89, 1H), 136.25, 6.26-6.20 (m, 1H), 4.22 (m,134.03, 1H) 133.88, 132.23, 131.23, 131.18, 129.20, 126.17, 125.04,124.99 DC47 139-141 474.16 8.51 (s, 1H), 8.14 (s, ([M − H]⁻) 1H), 7.75(s, 1H), 7.5 (m, 2H), 7.4 (s, 1H), 7.30 (m, 2H), 6.60 (d, J = 16.0 Hz,1H), 6.50 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H) DC48 124-126 414.058.69 (s, 1H), 8.14 (s, [M − H]⁻ 1H), 7.96 (d, J = 4.8 Hz, 1H), 7.39-7.27(m, 5H), 6.95 (d, J = 16.0 Hz, 1H), 6.51 (dd, J = 16.0, 7.6 Hz, 1H),4.13 (m, 1H) DC49 81-83 463.96 8.57 (s, 1H), 8.14 (s, [M − H]⁻ 1H), 7.60(m, 2H), 7.44 (m, 3H), 6.95 (d, J = 16.0 Hz, 1H), 6.51 (dd, J = 16.0,7.6 Hz, 1H), 4.13 (m, 1H) DC50 140-143 430.07 8.56 (s, 1H), 8.13 (s,1110, 803 [M − H]⁻) 1H), 7.59 (d, J = 1.2 Hz, 2H), 7.44 (m, 2H), 7.28(m, 2H), 6.61 (d, J = 16.0 Hz, 1H), 6.47 (dd, J = 16.0, 8.0 Hz, 1H),4.15 (m, 1H) DC51 118-121 464.22 8.32 (s, 1H), 8.15 (s, ([M − H]⁻) 1H),7.82 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.41(s, 1H), 7.29 (s, 2H), 6.70 (d, J = 15.6 Hz, 1H), 6.50 (dd, J = 15.6,8.0 Hz, 1H), 4.20 (m, 1H) DC52 9.99 (s, 1H), 8.42 (s, 3123, 3079, 1H),8.12 (s, 1H), 2925, 1692, 8.01 (s, 1H), 7.68 (m, 1H), 1571, 1512, 7.44(m, 1H), 7.33 (m, 1253, 1164, 1H), 7.22 (s, 2H), 1111 6.62 (d, J = 16.7Hz, 1H), 6.45 (dd, J = 16.7, 9.3 Hz, 1H), 4.10 (m, 1H) DC53 8.30 (m,1H), 8.00 (br s, 3250, 3043, 1H), 7.75 (m, 1H), 1683, 1116 7.68 (m, 1H),7.55 (m, 1H), 7.36 (m, 1H), 7.28 (m, 2H), 6.70 (m, 1H), 6.58 (br s, 1H),6.33 (m, 1H), 5.88 (m, 2H), 4.10 (m, 1H) DC54 56-58 441.07 8.40 (s, 1H),8.13 (s, ([M − H]⁻) 1H), 8.02 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.59(d, J = 8.0 Hz, 1H), 7.4 (s, 1H), 7.29 (m, 2H), 6.69 (d, J = 15.6 Hz,1H), 6.57 (dd, J = 15.6, 7.8 Hz, 1H), 4.15 (m, 1H) DC55 412.97 8.37 (s,1H), 8.18 (s, ([M + H]⁺) 1H), 7.39 (s, 1H), 7.30 (m, 2H), 7.19 (d, J =8.0 Hz, 1H), 6.90 (m, 2H), 6.55 (d, J = 15.6 Hz, 1H), 6.38 (dd, J =15.6, 8.2 Hz, 1H), 4.20 (m, 1H), 2.50 (br s, 2H) DC56 175-177 453 9.59(br s, 1H), 8.55 (s, ([M − H]⁻) 1H), 8.47 (s, 2H), 8.23 (s, 1H), 7.30(m, 4H), 6.62 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H),4.15 (m, 1H), 2.20 (s, 3H) DC57 426.0627 8.33 (s, 1H), 8.16 (s, 3342,3112, (426.0626) 1H), 7.38 (s, 1H), 2931, 1606, 7.29 (s, 2H), 7.15 (d, J= 7.6 Hz, 1583, 1574, 1H), 6.80 (d, J = 7.6 Hz, 1528, 1153 1H), 6.74 (m,1H), 6.60 (d, J = 15.6 Hz, 1H), 6.35 (dd, J = 15.6, 8.4 Hz, 1H), 5.40(br s, 1H), 4.15 (m, 1H), 2.90 (s, 3H) DC58 94-97 440.0424 (DMSO-d₆)8.76 (s, 3403, 3304, (440.0419) 1H), 8.16 (s, 1H), 3178, 1674, 7.90 (brs, 1H), 7.83 (s, 1H), 1571, 1169, 7.70 (d, J = 7.9 Hz, 1H), 11087.71-7.67 (m, 3H), 7.58 (d, J = 7.9 Hz, 1H), 7.52 (br s, 1H), 7.00 (dd,J = 15.8, 8.7 Hz, 1H), 6.85 (d, J = 15.8 Hz, 1H), 4.85 (m, 1H) DC5987-90 (DMSO-d₆) 9.00 (s, 1H), 8.63 (s, 1H), 8.17 (s, 1H), 7.70-7.59 (m,5H), 7.00 (dd, J = 16.2, 9.7 Hz, 1H), 6.85 (d, J = 16.2 Hz, 1H), 5.90(br s 2H), 4.83 (m, 1H) DC60 469.0577 8.32 (s, 1H), 8.10 (s, 2987, 1725,(469.0572) 1H), 7.97 (s, 1H), 1518, 1275, 7.65 (d, J = 8.1 Hz, 1H),1166, 1113 7.47 (d, J = 8.1 Hz, 1H), 7.40 (m, 1H), 7.28 (s, 2H), 6.62(d, J = 16.5 Hz, 1H), 6.49 (dd, J = 16.5, 7.7 Hz, 1H), 4.23-4.04 (m,3H), 1.15 (t, J = 8.0 Hz, 3H) DC61 130-132 442.15 (DMSO-d₆) 9.90 (s,([M + H]⁺) 1H), 8.17 (s, 1H), 8.15 (m, 1H), 7.90 (m, 1H), 7.71 (m, 2H),7.67 (m, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.03 (dd, J = 16.5, 8.3 Hz, 1H),6.62 (d, J = 16.5 Hz, 1H), 4.87 (m, 1H) DC62 412.10 8.27 (s, 1H), 8.23(s, 1513, 1252, ([M + H]⁺) 1H), 7.40 (m, 3H), 1166, 1112, 7.30 (m, 3H),6.64 (d, J = 16.0 Hz, 801 1H), 6.45 (dd, J = 16.0, 8.0 Hz, 1H), 4.19 (m,1H), 2.21 (s, 3H) DC63 446.01 8.26 (s, 1H), 8.12 (s, 2928, ([M + H]⁺)1H), 7.42 (s, 2H), 2525, 1249, 7.18-7.28 (m, 3H), 6.62 (d, J = 15.6 Hz,1169, 1114, 1H), 809 6.39 (dd, J = 15.6, 9.4 Hz, 1H), 4.10 (m, 1H), 2.25(s, 3H) DC64 475.03 8.84 (d, J = 5.8 Hz, 2H), 1683, 1167, ([M + H]⁺)8.33 (s, 1H), 8.20 (s, 650, 479 1H), 7.75 (m, 1H), 7.60 (d, J = 28.6 Hz,1H), 7.58-7.48 (m, 3H), 7.42 (m, 1H), 7.28 (s, 2H), 6.71 (d, J = 16.9Hz, 1H), 6.39 (dd, J = 16.9, 8.2 Hz, 1H), 4.15 (m, 1H) DC65 412.05 8.55(s, 1H), 8.12 (s, 722, 111 ([M + H]⁺) 1H), 7.55 (m, 3H), 7.39 (m, 1H),7.30 (d, J = 1.6 Hz, 1H), 6.85 (d, J = 16.0 Hz, 1H), 6.41 (dd, J = 16.0,8.0 Hz, 1H), 4.17 (m, 1H), 2.40 (s, 3H) DC66 60-61 468.26 8.59 (s, 1H),8.14 (s, ([M + H]⁺) 1H), 7.94 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.61(d, J = 8.0 Hz, 1H), 7.43 (s, 2H), 7.23 (d, J = 16.0 Hz, 1H), 6.41 (dd,J = 16.0, 8.0 Hz, 1H), 4.20 (m, 1H) DC67 133-134 432.30 8.59 (s, 1H),8.12 (s, 800, 114 ([M + H]⁺) 1H), 7.78 (br s, 1H), 7.71 (m, 1H), 7.62(m, 1H), 7.39 (s, 1H), 7.32 (s, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.43(dd, J = 16.0, 8.0 Hz, 1H), 0.21 (m, 1H) DC68 412.03 8.71 (s, 1H), 8.18(s, ([M + H]⁺) 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H),7.37 (s, 1H), 7.28 (m, 2H), 6.08 (d, J = 16.0 Hz, 1H), 4.26 (m, 1H),2.05 (s, 3H) DC69 162-168 414.03 8.56 (s, 1H), 8.11 (s, ([M + H]⁺) 1H),7.70 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.54 (m, 2H), 7.40(m, 1H), 6.91 (d, J = 16.5 Hz, 1H), 6.66 (d, J = 16.5 Hz, 1H) DC7099-103 428.05 8.58 (s, 1H), 8.13 (s, ([M + H]⁺) 1H), 7.73 (d, J = 8.7Hz, 2H), 7.60 (d, J = 8.7 Hz, 2H), 7.46 (m, 2H), 7.42 (m, 1H), 6.85 (d,J = 16.2 Hz, 1H), 6.40 (d, J = 16.2 Hz, 1H), 3.42 (s, 3H) ¹ ¹H NMRspectral data were acquired using a 400 MHz instrument in CDCl₃ exceptwhere noted. HRMS data are noted observed value (theoretical value).

TABLE 3 Assays Results Compound BAW CEW GPA Number Rating Rating RatingAC1 D D B AC2 C C C AC3 D D B AC4 D A B AC5 D D B AC6 D A B AC7 A A BAC8 D B B AC9 A A B AC10 A A B AC11 A A D AC12 A A D AC13 A A B AC14 A BD AC15 A A B AC16 A A C AC17 A A B AC18 A A B AC19 D D B AC20 A A C AC21D D C AC22 A A D AC23 A A B AC24 A A D AC25 A A D AC26 A A B AC27 A A BAC28 A A B AC29 A A B AC30 A A B AC31 A A B AC32 A A B AC33 A A B AC34 AA B AC35 A A C AC36 A A B AC37 A A B AC38 A A C AC39 A A C AC40 A A DAC41 A D D AC42 A D D AC43 A A B AC44 A A B AC45 A A D AC46 A A D AC47 DD B AC48 A A B AC49 A A B AC50 A D B AC51 A A B AC52 A A B AC53 A A BAC54 A A B AC57 A A B AC58 A A B AC59 A A B AC60 A A B AC61 A A B AC62 AA D AC63 A A B AC64 A A B AC65 A A B AC66 A A B AC67 A A B AC68 A A DAC69 A A A AC70 D D B AC71 A A B AC72 A A B AC75 A A B AC76 A A D AC77 AA B AC78 A A A AC79 A A A AC80 A A B AC81 A D D AC82 A A B AC83 A A BAC84 A A D AC85 A A B AC86 A A D AC87 A A B AC89 A A B AC90 A A C AC91 AA C AC92 A A C AC93 A D C AC94 D B B AC95 A A C AC96 D D C AC97 D D CAC98 A A C AC99 A A C AC100 C C C AC101 D D C AC102 D A C AC103 A A DAC104 A A B AC105 A A D AC106 A A B AC107 B A D AC108 B D D AC109 D D CAC110 A A C AC111 A A C AC112 A A C AC113 B A D AC114 A B D AC115 A A DAC116 C C C AC117 A D B AC118 A D D BC1 A A D BC2 A A D BC3 A A D BC4 AA B BC5 A A B BC6 A A D BC7 A A D BC8 A A B BC9 A A D BC10 A A B BC11 CC C BC12 C C C BC13 A A D BC14 A D D CC1 D D D CC2 A A B CC3 A A D CC4 AB B CC5 A A B CC6 A A B CC7 A A B CC8 A A D CC9 A A B CC10 A A B CC11 AA B CC12 D D B CC13 A A B CC14 A D D CC15 A A B CC16 A A B CC17 A A BCC18 A A B CC19 A A B CC20 A A D CC21 A A D CC22 A A B CC23 A A B CC24 AA D CC25 A A B CC26 A D B CC27 A A D CC28 A A D CC29 A A B CC30 A A DCC31 B D C CC32 A A B CC33 A A B CC34 A A B CC35 D D D CC36 A A D CC37 AA D CC38 A A D CC39 D D B CC40 D A D CC41 D D B CC42 D D D CC43 A B BCC44 A A B CC45 A A D CC46 D A C CC47 D D C CC48 D D C CC49 D D D CC50 AA D CC51 A A D CC52 A D D CC53 D D B CC54 A A C DC1 A A D DC2 D D C DC3B D C DC4 A D C DC5 D D C DC6 D D C DC7 A D C DC8 A D C DC9 D D C DC10 DD C DC11 A D C DC12 A A B DC13 A A C DC14 D D C DC15 D D C DC16 A A CDC17 A A C DC18 A A C DC19 A A C DC20 A D C DC21 D D C DC22 D D C DC23 DA C DC24 D D C DC25 D D C DC26 D D C DC27 D D C DC28 A A B DC29 A A CDC30 A A C DC31 A A B DC32 D D C DC33 A A C DC34 A A B DC35 A A B DC36 DD C DC37 A A C DC38 A A C DC39 A A C DC40 A A C DC41 A A C DC42 A A CDC43 A A C DC44 A A C DC45 A A C DC46 A A C DC47 A A C DC48 A A C DC49 AA C DC50 A A C DC51 A A C DC52 D D C DC53 D A C DC54 D D C DC55 D D CDC56 D D C DC57 A A C DC58 D D C DC59 D D C DC60 A A C DC61 D D C DC62 AA C DC63 A A C DC64 D D C DC65 D A C DC66 A A C DC67 A A C DC68 A A CDC69 D D C DC70 A A C

We claim:
 1. A composition comprising a molecule according to FormulaOne:

wherein: (a) R1 is H, F, Cl, Br, or I; (b) R2 is H, F, Cl, Br, or I; (c)R3 is H, F, Cl, Br, or I; (d) R4 is H, F, Cl, Br, or I; (e) R5 is H, F,Cl, Br, or I; (f) R6 is a (C₁-C₈)haloalkyl; (g) R7 is H; (h) R8 is H;(i) R9 is H; (j) R10 is F, Cl, Br, I, (C₁-C₈)alkyl, or halo(C₁-C₈)alkyl;(k) R11 is C(═O)N(R14)((C₁-C₈)alkylC(═O)(R15); (l) R12 is H; (m) R13 isH; (n) R14 is H; (o) R15 is N(R16)(R17); (p) R16 is H; (q) R17 ishalo(C₁-C₈)alkyl; (r) X1 is CR12; (s) X2 is CR13; and (t) X3 is CR9. 2.A molecule according to claim 1 wherein R2 and R4 are selected from F,Cl, Br, I, CN, and NO₂ and R1, R3, and R5 are H.
 3. A molecule accordingto claim 1 wherein R2, R3, and R4 are selected from F, Cl, Br, I, CN,and NO₂ and R1, and R5 are H.
 4. A molecule according to claim 1 whereinR2, R3, and R4 are independently selected from F and Cl and R1 and R5are H.
 5. A molecule according to claim 1 wherein R6 is trifluoromethyl.6. A molecule according to claim 1 wherein R10 is Cl, Br, CH₃, or CF₃.7. A molecule according to claim 1 wherein R11 isC(═O)N(H)(CH₂C(═O)N(H)(CH₂CF₃)).
 8. A molecule according to claim 1wherein R15 is CH₂C(═O)N(H)(CH₂CF₃).
 9. A molecule according to claim 1having one of the following structures


10. A composition according to claim 1 further comprising: (a) one ormore compounds having acaricidal, algicidal, avicidal, bactericidal,fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal,rodenticidal, or virucidal properties; or (b) one or more compounds thatare antifeedants, bird repellents, chemosterilants, herbicide safeners,insect attractants, insect repellents, mammal repellents, matingdisrupters, plant activators, plant growth regulators, or synergists; or(c) both (a) and (b).
 11. A composition according to claim 1 whereinfurther comprising one or more compounds selected from:(3-ethoxypropyl)mercury bromide, 1,2-dichloropropane,1,3-dichloropropene, 1-methylcyclopropene, 1-naphthol,2-(octylthio)ethanol, 2,3,5-tri-iodobenzoic acid, 2,3,6-TBA,2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6-TBA-potassium,2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2-butoxypropyl, 2,4,5-T-2-ethylhexyl,2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-T-butotyl,2,4,5-T-butyl, 2,4,5-T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl,2,4,5-T-methyl, 2,4,5-T-pentyl, 2,4,5-T-sodium,2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4-D,2,4-D-2-butoxypropyl, 2,4-D-2-ethylhexyl, 2,4-D-3-butoxypropyl,2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium,2,4-DB-isoctyl, 2,4-DB-potassium, 2,4-DB-sodium, 2,4-D-butotyl,2,4-D-butyl, 2,4-D-diethylammonium, 2,4-D-dimethylammonium,2,4-D-diolamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4-D-ethyl,2,4-D-heptylammonium, 2,4-D-isobutyl, 2,4-D-isoctyl, 2,4-D-isopropyl,2,4-D-isopropylammonium, 2,4-D-lithium, 2,4-D-meptyl, 2,4-D-methyl,2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,4-D-propyl, 2,4-D-sodium,2,4-D-tefuryl, 2,4-D-tetradecylammonium, 2,4-D-triethylammonium,2,4-D-tris(2-hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP,2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP,4-aminopyridine, 4-CPA, 4-CPA-potassium, 4-CPA-sodium, 4-CPB, 4-CPP,4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate,8-phenylmercurioxyquinoline, abamectin, abscisic acid, ACC, acephate,acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole,acibenzolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl,acifluorfen-sodium, aclonifen, acrep, acrinathrin, acrolein,acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc, alachlor,alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin,allethrin, allicin, allidochlor, allosamidin, alloxydim,alloxydim-sodium, allyl alcohol, allyxycarb, alorac, alpha-cypermethrin,alpha-endosulfan, ametoctradin, ametridione, ametryn, amibuzin,amicarbazone, amicarthiazol, amidithion, amidoflumet, amidosulfuron,aminocarb, aminocyclopyrachlor, aminocyclopyrachlor-methyl,aminocyclopyrachlor-potassium, aminopyralid, aminopyralid-potassium,aminopyralid-tris(2-hydroxypropyl)ammonium, amiprofos-methyl,amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole,ammonium sulfamate, ammonium α-naphthaleneacetate, amobam, ampropylfos,anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone,antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam,asulam-potassium, asulam-sodium, athidathion, atraton, atrazine,aureofungin, aviglycine, aviglycine hydrochloride, azaconazole,azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos-ethyl,azinphos-methyl, aziprotryne, azithiram, azobenzene, azocyclotin,azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate,barium polysulfide, barthrin, BCPC, beflubutamid, benalaxyl,benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolin-ethyl,benazolin-potassium, bencarbazone, benclothiaz, bendiocarb, benfluralin,benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos,benquinox, bensulfuron, bensulfuron-methyl, bensulide, bensultap,bentaluron, bentazone, bentazone-sodium, benthiavalicarb,benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox,benzadox-ammonium, benzalkonium chloride, benzamacril,benzamacril-isobutyl, benzamorf, benzfendizone, benzipram,benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid,benzoximate, benzoylprop, benzoylprop-ethyl, benzthiazuron, benzylbenzoate, benzyladenine, berberine, berberine chloride, beta-cyfluthrin,beta-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, bifenox,bifenthrin, bifujunzhi, bilanafos, bilanafos-sodium, binapacryl,bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin,bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac,bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen,blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid,brassinolide, brassinolide-ethyl, brevicomin, brodifacoum,brofenvalerate, brofluthrinate, bromacil, bromacil-lithium,bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos,bromoacetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT,bromofenoxim, bromophos, bromophos-ethyl, bromopropylate, bromothalonil,bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxyniloctanoate, bromoxynil-potassium, brompyrazon, bromuconazole, bronopol,bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundymixture, busulfan, butacarb, butachlor, butafenacil, butamifos,butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron,butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin,butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos,cafenstrole, calcium arsenate, calcium chlorate, calcium cyanamide,calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor,captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam,carbendazim, carbendazim benzenesulfonate, carbendazim sulfite,carbetamide, carbofuran, carbon disulfide, carbon tetrachloride,carbophenothion, carbosulfan, carboxazole, carboxide, carboxin,carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartaphydrochloride, carvacrol, carvone, CDEA, cellocidin, CEPC, ceralure,Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone,chlomethoxyfen, chloralose, chloramben, chloramben-ammonium,chloramben-diolamine, chloramben-methyl, chloramben-methylammonium,chloramben-sodium, chloramine phosphorus, chloramphenicol,chloraniformethan, chloranil, chloranocryl, chlorantraniliprole,chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside,chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane,chlordecone, chlordimeform, chlordimeform hydrochloride,chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac,chlorfenac-ammonium, chlorfenac-sodium, chlorfenapyr, chlorfenazole,chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide,chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren,chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon,chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequatchloride, chlomidine, chlornitrofen, chlorobenzilate,chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron,chloroneb, chlorophacinone, chlorophacinone-sodium, chloropicrin,chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron,chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim,chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos,chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal,chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos,chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II,cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide,cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop,clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium,clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone,clomeprop, cloprop, cloproxydim, clopyralid, clopyralid-methyl,clopyralid-olamine, clopyralid-potassium,clopyralid-tris(2-hydroxypropyl)ammonium, cloquintocet,cloquintocet-mexyl, cloransulam, cloransulam-methyl, closantel,clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA,codlelure, colophonate, copper acetate, copper acetoarsenite, copperarsenate, copper carbonate, basic, copper hydroxide, copper naphthenate,copper oleate, copper oxychloride, copper silicate, copper sulfate,copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl,coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol,crimidine, crotamiton, crotoxyphos, crufomate, cryolite, cue-lure,cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide,cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate,cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide,cyclethrin, cycloate, cycloheximide, cycloprate, cycloprothrin,cyclosulfamuron, cycloxaprid, cycloxydim, cycluron, cyenopyrafen,cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl,cyhalothrin, cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil,cyometrinil, cypendazole, cypermethrin, cyperquat, cyperquat chloride,cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil,cyprofuram, cypromid, cyprosulfamide, cyromazine, cythioate, daimuron,dalapon, dalapon-calcium, dalapon-magnesium, dalapon-sodium, daminozide,dayoutong, dazomet, dazomet-sodium, DB CP, d-camphor, DCIP, DCPTA, DDT,debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor,deltamethrin, demephion, demephion-O, demephion-S, demeton,demeton-methyl, demeton-O, demeton-O-methyl, demeton-S,demeton-S-methyl, demeton-S-methylsulphon, desmedipham, desmetryn,d-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos,diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate,dicamba, dicamba-diglycolamine, dicamba-dimethylammonium,dicamba-diolamine, dicamba-isopropylammonium, dicamba-methyl,dicamba-olamine, dicamba-potassium, dicamba-sodium, dicamba-trolamine,dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone,dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl,dichlormate, dichlormid, dichlorophen, dichlorprop,dichlorprop-2-ethylhexyl, dichlorprop-butotyl,dichlorprop-dimethylammonium, dichlorprop-ethylammonium,dichlorprop-isoctyl, dichlorprop-methyl, dichlorprop-P,dichlorprop-P-2-ethylhexyl, dichlorprop-P-dimethylammonium,dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline,diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine,diclomezine-sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl,dicrotophos, dicyclanil, dicyclonon, dieldrin, dienochlor, diethamquat,diethamquat dichloride, diethatyl, diethatyl-ethyl, diethofencarb,dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum,difenoconazole, difenopenten, difenopenten-ethyl, difenoxuron,difenzoquat, difenzoquat metilsulfate, difethialone, diflovidazin,diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium,diflumetorim, dikegulac, dikegulac-sodium, dilor, dimatif, dimefluthrin,dimefox, dimefuron, dimepiperate, dimetachlone, dimetan, dimethacarb,dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin,dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate,dimethyl phthalate, dimethylvinphos, dimetilan, dimexano, dimidazon,dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, diniconazole,diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6,dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinosebacetate, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium,dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb acetate,dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion,diphacinone, diphacinone-sodium, diphenamid, diphenyl sulfone,diphenylamine, dipropalin, dipropetryn, dipyrithione, diquat, diquatdibromide, disparlure, disul, disulfiram, disulfoton, disul-sodium,ditalimfos, dithianon, dithicrofos, dithioether, dithiopyr, diuron,d-limonene, DMPA, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium,dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicinhydrochloride, dodicin-sodium, dodine, dofenapyn, dominicalure,doramectin, drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone,edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate,EMPC, empenthrin, endosulfan, endothal, endothal-diammonium,endothal-dipotassium, endothal-disodium, endothion, endrin,enestroburin, EPN, epocholeone, epofenonane, epoxiconazole,eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan,esdépalléthrine, esfenvalerate, esprocarb, etacelasil, etaconazole,etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron,ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron,ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol,ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen,ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethylformate, ethyl α-naphthaleneacetate, ethyl-DDD, ethylene, ethylenedibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercurybromide, ethylmercury chloride, ethylmercury phosphate, etinofen,etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos,eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos,fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazole,fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos,fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan,fenitrothion, fenjuntong, fenobucarb, fenoprop, fenoprop-3-butoxypropyl,fenoprop-butometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoctyl,fenoprop-methyl, fenoprop-potassium, fenothiocarb, fenoxacrim,fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P,fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb, fenpiclonil,fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine,fenpyroximate, fenridazon, fenridazon-potassium, fenridazon-propyl,fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop-ethyl,fenthion, fenthion-ethyl, fentin, fentin acetate, fentin chloride,fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron TCA,fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil, flamprop,flamprop-isopropyl, flamprop-M, flamprop-methyl, flamprop-M-isopropyl,flamprop-M-methyl, flazasulfuron, flocoumafen, flometoquin, flonicamid,florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl,fluazifop-P, fluazifop-P-butyl, fluazinam, fluazolate, fluazuron,flubendiamide, flubenzimine, flucarbazone, flucarbazone-sodium,flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate,fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim,flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl,flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin,flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph,fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamid,fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl,fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole,fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate,flupropanate-sodium, flupyradifurone, flupyrsulfuron,flupyrsulfuron-methyl, flupyrsulfuron-methyl-sodium, fluquinconazole,flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone,flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl,flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide,fluthiacet, fluthiacet-methyl, flutianil, flutolanil, flutriafol,fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen,fomesafen-sodium, fonofos, foramsulfuron, forchlorfenuron, formaldehyde,formetanate, formetanate hydrochloride, formothion, formparanate,formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl,fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan,frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling,fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr,furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin,furfural, furilazole, furmecyclox, furophanate, furyloxyfen,gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid, gibberellins,gliftor, glufosinate, glufosinate-ammonium, glufosinate-P,glufosinate-P-ammonium, glufosinate-P-sodium, glyodin, glyoxime,glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium,glyphosate-isopropylammonium, glyphosate-monoammonium,glyphosate-potassium, glyphosate-sesquisodium, glyphosate-trimesium,glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatineacetates, halacrinate, halfenprox, halofenozide, halosafen,halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop,haloxyfop-etotyl, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-etotyl,haloxyfop-P-methyl, haloxyfop-sodium, HCH, hemel, hempa, HEOD,heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone,hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole,hexaflumuron, hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos,hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo,hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanide,hydroprene, hymexazol, hyquincarb, IAA, IBA, icaridin, imazalil,imazalil nitrate, imazalil sulfate, imazamethabenz,imazamethabenz-methyl, imazamox, imazamox-ammonium, imazapic,imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin,imazaquin-ammonium, imazaquin-methyl, imazaquin-sodium, imazethapyr,imazethapyr-ammonium, imazosulfuron, imibenconazole, imicyafos,imidacloprid, imidaclothiz, iminoctadine, iminoctadine triacetate,iminoctadine trialbesilate, imiprothrin, inabenfide, indanofan,indaziflam, indoxacarb, inezin, iodobonil, iodocarb, iodomethane,iodosulfuron, iodosulfuron-methyl, iodosulfuron-methyl-sodium,iofensulfuron, iofensulfuron-sodium, ioxynil, ioxynil octanoate,ioxynil-lithium, ioxynil-sodium, ipazine, ipconazole, ipfencarbazone,iprobenfos, iprodione, iprovalicarb, iprymidam, ipsdienol, ipsenol,IPSP, isamidofos, isazofos, isobenzan, isocarbamid, isocarbophos,isocil, isodrin, isofenphos, isofenphos-methyl, isolan, isomethiozin,isonoruron, isopolinate, isoprocarb, isopropalin, isoprothiolane,isoproturon, isopyrazam, isopyrimol, isothioate, isotianil, isouron,isovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl,isoxaflutole, isoxapyrifop, isoxathion, ivermectin, izopamfos,japonilure, japothrins, jasmolin I, jasmolin II, jasmonic acid,jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan,jiecaoxi, jodfenphos, juvenile hormone I, juvenile hormone II, juvenilehormone III, kadethrin, karbutilate, karetazan, karetazan-potassium,kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox,ketospiradox-potassium, kinetin, kinoprene, kresoxim-methyl, kuicaoxi,lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil,lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure,looplure, lufenuron, lvdingjunzhi, lvxiancaolin, lythidathion, MAA,malathion, maleic hydrazide, malonoben, maltodextrin, MAMA, mancopper,mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA,MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium,MCPA-diolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl,MCPA-methyl, MCPA-olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl,MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil,mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl,mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl,mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P-2-ethylhexyl,mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoprop-potassium,mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform,medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr,mefenpyr-diethyl, mefluidide, mefluidide-diolamine,mefluidide-potassium, megatomoic acid, menazon, mepanipyrim,meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride,mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride,mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron,mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone,metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop,metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron,metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron,methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole,methfuroxam, methidathion, methiobencarb, methiocarb,methiopyrisulfuron, methiotepa, methiozolin, methiuron, methocrotophos,methometon, methomyl, methoprene, methoprotryne, methoquin-butyl,methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methylapholate, methyl bromide, methyl eugenol, methyl iodide, methylisothiocyanate, methylacetophos, methylchloroform, methyldymron,methylene chloride, methylmercury benzoate, methylmercury dicyandiamide,methylmercury pentachlorophenoxide, methylneodecanamide, metiram,metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb,metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone,metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos,mexacarbate, mieshuan, milbemectin, milbemycin oxime, milneb, mipafox,mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron,monochloroacetic acid, monocrotophos, monolinuron, monosulfuron,monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquatdichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid,moxidectin, MSMA, muscalure, myclobutanil, myclozolin,N-(ethylmercury)-p-toluenesulphonanilide, nabam, naftalofos, naled,naphthalene, naphthaleneacetamide, naphthalic anhydride, naphthoxyaceticacids, naproanilide, napropamide, naptalam, naptalam-sodium, natamycin,neburon, niclosamide, niclosamide-olamine, nicosulfuron, nicotine,nifluridide, nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin,nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothal-isopropyl,norbormide, norflurazon, nomicotine, noruron, novaluron, noviflumuron,nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace,omethoate, orbencarb, orfralure, ortho-dichlorobenzene, orthosulfamuron,oryctalure, orysastrobin, oryzalin, osthol, ostramone, oxabetrinil,oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl, oxapyrazon,oxapyrazon-dimolamine, oxapyrazon-sodium, oxasulfuron, oxaziclomefone,oxine-copper, oxolinic acid, oxpoconazole, oxpoconazole fumarate,oxycarboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyfluorfen,oxymatrine, oxytetracycline, oxytetracycline hydrochloride,paclobutrazol, paichongding, para-dichlorobenzene, parafluron, paraquat,paraquat dichloride, paraquat dimetilsulfate, parathion,parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid,penconazole, pencycuron, pendimethalin, penflufen, penfluron,penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin,pentoxazone, perfluidone, permethrin, pethoxamid, phenamacril, phenazineoxide, phenisopham, phenkapton, phenmedipham, phenmedipham-ethyl,phenobenzuron, phenothrin, phenproxide, phenthoate, phenylmercuriurea,phenylmercury acetate, phenylmercury chloride, phenylmercury derivativeof pyrocatechol, phenylmercury nitrate, phenylmercury salicylate,phorate, phosacetim, phosalone, phosdiphen, phosfolan, phosfolan-methyl,phosglycin, phosmet, phosnichlor, phosphamidon, phosphine, phosphocarb,phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram,picloram-2-ethylhexyl, picloram-isoctyl, picloram-methyl,picloram-olamine, picloram-potassium, picloram-triethylammonium,picloram-tris(2-hydroxypropyl)ammonium, picolinafen, picoxystrobin,pindone, pindone-sodium, pinoxaden, piperalin, piperonyl butoxide,piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide,piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl,pirimiphos-methyl, plifenate, polycarbamate, polyoxins, polyoxorim,polyoxorim-zinc, polythialan, potassium arsenite, potassium azide,potassium cyanate, potassium gibberellate, potassium naphthenate,potassium polysulfide, potassium thiocyanate, potassiumα-naphthaleneacetate, pp′-DDT, prallethrin, precocene I, precocene II,precocene III, pretilachlor, primidophos, primisulfuron,primisulfuron-methyl, probenazole, prochloraz, prochloraz-manganese,proclonol, procyazine, procymidone, prodiamine, profenofos, profluazol,profluralin, profluthrin, profoxydim, proglinazine, proglinazine-ethyl,prohexadione, prohexadione-calcium, prohydrojasmon, promacyl, promecarb,prometon, prometryn, promurit, propachlor, propamidine, propamidinedihydrochloride, propamocarb, propamocarb hydrochloride, propanil,propaphos, propaquizafop, propargite, proparthrin, propazine,propetamphos, propham, propiconazole, propineb, propisochlor, propoxur,propoxycarbazone, propoxycarbazone-sodium, propyl isome,propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin,prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothiocarbhydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute,proxan, proxan-sodium, prynachlor, pydanon, pymetrozine, pyracarbolid,pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen-ethyl,pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole,pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl,pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II,pyrethrins, pyribambenz-isopropyl, pyribambenz-propyl, pyribencarb,pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl,pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon,pyriftalid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl,pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole,pyripropanol, pyriproxyfen, pyrithiobac, pyrithiobac-sodium, pyrolan,pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia,quinacetol, quinacetol sulfate, quinalphos, quinalphos-methyl,quinazamid, quinclorac, quinconazole, quinmerac, quinoclamine,quinonamid, quinothion, quinoxyfen, quintiofos, quintozene, quizalofop,quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl,quizalofop-P-tefuryl, quwenzhi, quyingding, rabenzazole, rafoxanide,rebemide, resmethrin, rhodethanil, rhodojaponin-III, ribavirin,rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong,salicylanilide, sanguinarine, santonin, schradan, scilliroside,sebuthylazine, secbumeton, sedaxane, selamectin, semiamitraz,semiamitraz chloride, sesamex, sesamolin, sethoxydim, shuangjiaancaolin,siduron, siglure, silafluofen, silatrane, silica gel, silthiofam,simazine, simeconazole, simeton, simetryn, sintofen, SMA, S-metolachlor,sodium arsenite, sodium azide, sodium chlorate, sodium fluoride, sodiumfluoroacetate, sodium hexafluorosilicate, sodium naphthenate, sodiumorthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide,sodium thiocyanate, sodium α-naphthaleneacetate, sophamide, spinetoram,spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine,streptomycin, streptomycin sesquisulfate, strychnine, sulcatol,sulcofuron, sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone,sulfiram, sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron,sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid,sulfuryl fluoride, sulglycapin, sulprofos, sultropen, swep,tau-fluvalinate, tavron, tazimcarb, TCA, TCA-ammonium, TCA-calcium,TCA-ethadyl, TCA-magnesium, TCA-sodium, TDE, tebuconazole, tebufenozide,tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron,tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin,tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim,terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton,terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane,tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin,tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate,thenylchlor, theta-cypermethrin, thiabendazole, thiacloprid,thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr,thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone,thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl,thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam,thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole-copper,thiodicarb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon,thionazin, thiophanate, thiophanate-methyl, thioquinox,thiosemicarbazide, thiosultap, thiosultap-diammonium,thiosultap-disodium, thiosultap-monosodium, thiotepa, thiram,thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid,tirpate, tolclofos-methyl, tolfenpyrad, tolylfluanid, tolylmercuryacetate, topramezone, tralkoxydim, tralocythrin, tralomethrin,tralopyril, transfluthrin, transpermethrin, tretamine, triacontanol,triadimefon, triadimenol, triafamone, tri-allate, triamiphos,triapenthenol, triarathene, triarimol, triasulfuron, triazamate,triazbutil, triaziflam, triazophos, triazoxide, tribenuron,tribenuron-methyl, tribufos, tributyltin oxide, tricamba, trichlamide,trichlorfon, trichlormetaphos-3, trichloronat, triclopyr,triclopyr-butotyl, triclopyr-ethyl, triclopyr-triethylammonium,tricyclazole, tridemorph, tridiphane, trietazine, trifenmorph,trifenofos, trifloxystrobin, trifloxysulfuron, trifloxysulfuron-sodium,triflumizole, triflumuron, trifluralin, triflusulfuron,triflusulfuron-methyl, trifop, trifop-methyl, trifopsime, triforine,trihydroxytriazine, trimedlure, trimethacarb, trimeturon, trinexapac,trinexapac-ethyl, triprene, tripropindan, triptolide, tritac,triticonazole, tritosulfuron, trunc-call, uniconazole, uniconazole-P,urbacide, uredepa, valerate, validamycin, valifenalate, valone,vamidothion, vangard, vaniliprole, vernolate, vinclozolin, warfarin,warfarin-potassium, warfarin-sodium, xiaochongliulin, xinjunan,xiwojunan, XMC, xylachlor, xylenols, xylylcarb, yishijing, zarilamid,zeatin, zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide,zinc thiazole, zineb, ziram, zolaprofos, zoxamide, zuomihuanglong,α-chlorohydrin, α-ecdysone, α-multistriatin, and α-naphthaleneaceticacid.
 12. A composition according to claim 1 further comprising anagriculturally acceptable carrier.
 13. A composition according to claim1 further comprising a biopesticide.
 14. A composition according toclaim 1 further comprising a compound having one or more of thefollowing modes of action: acetylcholinesterase inhibitor; sodiumchannel modulator; chitin biosynthesis inhibitor; GABA andglutamate-gated chloride channel antagonist; GABA and glutamate-gatedchloride channel agonist; acetylcholine receptor agonist; acetylcholinereceptor antagonist; MET I inhibitor; Mg-stimulated ATPase inhibitor;nicotinic acetylcholine receptor; Midgut membrane disrupter; oxidativephosphorylation disrupter, and ryanodine receptor (RyRs).
 15. Acomposition according to claim 1 further comprising a seed.
 16. Acomposition according to claim 1 further comprising a seed that has beengenetically modified to express one or more specialized traits.
 17. Aprocess comprising applying a composition according to claim 1, to anarea to control a pest, in an amount sufficient to control such pest.18. A process according to claim 17 wherein said pest is selected frombeetles, earwigs, cockroaches, flies, aphids, scales, whiteflies,leafhoppers, ants, wasps, termites, moths, butterflies, lice,grasshoppers, locusts, crickets, fleas, thrips, bristletails, mites,ticks, nematodes, and symphylans.
 19. A process according to claim 17further comprising applying said composition to a genetically modifiedplant that has been genetically modified to express one or morespecialized traits.
 20. A composition according to claim 12 where saidcomposition further comprise ammonium sulfate.